17-acetylgonanes and process therefor

ABSTRACT

COMPOUNDS OF THE 17-ACETYLGONANE SERIES AND D-HOMO ANALOGS THEREOF, PREFERABLY SUBSTITUTED AT C-13 WITH POLYCARBONALKYL, AND AT C-16 WITH (LOWER)ALKYL, OPTIONALLY SUBSTITUTED AT C-17 WITH HYDROXY, ALKANOYLOXY OR FORMYLOXY; OR OPTIONALLY UNSATURATED AT C16-C17 (I) ARE HORMONALLY-ACTIVE AND VALUABLE INTERMEDIATES FOR HORMONALLYACTIVE STEROIDS. COMPOUNDS (I) OF THE GON-4-EN-3-ONE SERIES, SUBSTITUTED AT C-16 BY ALKYL, OPTIONALLY SUBSTITUTED AT C-6 BY HALOGEN OR METHYL AND OPTIONALLY UNSATURATED AT -C2-C7- (IA) ARE PROGESTATIONALLY AND ANTI-ESTROGENICALLY ACTIVE. COMPOUNDS (I) OF THE GONA-1,3,5(10)-TRENE SERIES, SUBSTITUTED AT C-16 BY ALKYL (IC) ARE ESTROGENICALLY AND ANTI-LIPEMICALLY ACTIVE. THE 17-ACETYLGON-16-ENES, OPTIONALLY SUBSTITUTED AT C16 WITH (LOWER)ALKYL (IA) AND THE 17A-ACETYLGONAN-17B-OL, FORMATES OR ALKANOATES (IE) ARE PROVIDED BY HYDRATING THE CORRESPONDING 17-ETHYNYLGON-16-ENES (IIA) OR 17A-ETHYNYLGONAN-17B-OL, FORMATES OR ALKANOATES (IIB). COMPOUNDS (IIA) AND (IIB) ARE PROVIDED, RESPECTIVELY, BY (I) DEHYDRATING OR (II) ACYLATING THE CORRESPONDING 17A-ETHYNYLGONAN-17B-OLS. REACTION OF (ID) WITH DIAZOALKANES PROVIDES 16A,17A-AZO(LOWER)ALKYLENE COMPOUNDS (XI), WHICH ON DECOMPOSITION BY HEATING PRODUCE 17-ACETYL-16-ALKYLGON-16-ENES (II) PROVIDES THE 17-ACETYL16B-ALKYL SERIES (IN). REACTION OF (ID)WITH ALKYL GRIGNARD REAGENTS PROVIDES THE 17-ACETYL-16A-ALKYL SERIES (VIII). COMPOUNDS (ID) OF THE GON-4-EN-3-ONE SERIES ARE CONVERTED BY REDUCTION TO HORMONALLY-ACTIVE, ESPECIALLY PROGESTATIONALLY, ANTI-ESTROGENICALLY, AND ANTI-ANDROGENICALLY ACTIVE COMPOUNDS OF THE 17-ACETYLGON-4-EN-3-ONE SERIES, E.G., PROGESTERONE. MEANS ARE PROVIDED TO OBTAIN PROGESTATIONALLY ACTIVE COMPOUNDS OF THE 16-UNSUBSTITUTED-GON-4ENE SERIES COMPRISING REDUCING OR CLEAVING $1,3,4(10). COMPOUNDS (II) OR (IJ) FOLLOWED BY BIRCH REDUCTION IN THE ARING AND OXIDATION. MEANS ALSO ARE DESCRIBED FOR PROVIDING THE NEW GON-4-EN-3-ONE COMPOUNDS OF THIS INVENTION SUBSTITUTED AT C-16 BY ALKYL (IA) COMPRISING CONVERTING AN AROMATIC A-RING TO A $4-3-ONE; INTRODUCTION OF METHYL OR HALOGEN AT C6, INTRODUCTION OR UNSATURATION AT -C6-C7AND INTRODUCTION OF HYDROXY AND ALKANOYLOXY AT C17.

United States Patent f 3,775,443 17-ACETYLGONANES AND PROCESS THEREFOR Reinhardt P. Stein, Audubon, Herchel Smith, Bryn Mawr,

and Robert C. Smith, Malvern, Pa., assignors to American Home Products Corporation, New York, N.Y. No Drawing. Continuation-impart of application Ser. No.

857,557, Sept. 12, 1969, which is a continuation-inpart of application Ser. No. 748,594, July 30, 1968,

both now abandoned. This application Mar. 1, 1972,

Ser. No. 230,933

Int. Cl. C07c 169/10 US. Cl. 260-3974 37 Claims ABSTRACT OF THE DISCLOSURE Compounds of the 17-acetylgonane series, and D-homo analogs thereof, preferably substituted at C-l3 with polycarbonalkyl, and at C-16 with (lower)alkyl, optionally substituted at C17 with hydroxy, alkanoyloxy or formyloxy; or optionally unsaturated at Ole-C17 (I) are hormonally-active and valuable intermediates for hormonallyactive steroids. Compounds (I) of the g0n-4-en-3-one series, substituted at 0-16 by alkyl, optionally substituted at 0-6 by halogen or methyl and optionally unsaturated at C C (Ia) are progestationally and anti-estrogenically active. Compounds (I) of the gona-1,3,5(10)-triene series, substituted at C-16 by alkyl (Ie) are estrogenically and anti-lipemically active.

The 17-acetylgon-l6enes, optionally substituted at C with (lower)alkyl (Ia) and the 17a-acetylgonan-175-ol, formates or alkanoates (Ie) are provided by hydrating the corresponding l7-ethynylgon-16-enes (IIa) or 17m-ethynylgonan-17fl-ol, formates or alkanoates (IIb). Compounds (11a) and (11b) are provided, respectively, by (i) dehydrating or (ii) acylating the corresponding 17a-ethyny1- gonan-17fi-ols. Reaction of (Id) with diazoalkanes provides 16a,17rx-azo(lower)alkylene compounds (XI), which on decomposition by heating produce 17-acetyl-16- alkylgon-16-enes (II). Reduction of (II) provides the 17-acetyl- 16,8-alky1 series (In). Reaction of (Id) with alkyl Grignard reagents provides the -17-acetyl-16a-alkyl series (VIII).

Compounds (Id) of the gon-4-en3-one series are com verted by reduction to hormonally-active, especially progestationally, anti-estrogenically, and anti-androgenically active compounds of the l7-acetylgon-4-en-3-one series, e.g., progesterone. Means are provided to obtain progestationally active compounds of the 16-unsubstituted-gon-4- ene series comprising reducing or cleaving A Compounds (Ii) or (Ij) followed by Birch reduction in the A- ring and oxidation. Means also are described for providing the new gon-4-en-3-one compounds of this invention substituted at C-16 by alkyl (Ia) comprising converting an aromatic A-ring to a A -3-one; introduction of methyl or halogen at C introduction or unsaturation at -C C and introduction of hydroxy and alkanoyloxy at C This application is a continuation-in-part of copending application Ser. No. 857,557, filed Sept. 12, 1969, now abandoned, which in turn is a continuation-impart of application Ser. No. 748,594, filed July 30, 1968, now abandoned.

This invention is concerned generally with novel steroid compounds and with processes for preparing and using the same, and with useful intermediates therefor. More particularly, it relates to hormonally-active steroids of the 16-alkyl 13 polycarbonalkyl-l8-nor-pregn-4-en-3-one series, and 19-norand D-homo analogs thereof, and especially to the l7fl-acetyl-16-alkyl-l3-polycarbonalkylgon- 4-en-3-one and gona-l,3,5(10)-triene sub-genera thereof, and to intermediates therefor, particularly steroids of the 3,775,443 Patented Nov. 27, 1973 17-acetylgon-16-series, and 17-acetylgonan-l7fl-ol, alkanoate series, to D-homo-analogs thereof, to processes of ptroducing them and to novel and valuable processes using t em.

DESCRIPTION OF THE INVENTION The invention contemplates, in essence, 1st, steroid compounds of Formula I wherein R is polycarbon (lower)alkyl; n is I or 2; X is a radical containing at least eleven carbon atoms so arranged as to complete a steroid of the cyclopentanoperhydrophenanthrene series or a D-homo analog thereof; and C C is a divalent radical of the formulae:

a con c012 (E 3 "coca Y or wherein Y is hydrogen or CH R wherein R is hydrogen or (lower)alkyl; G is C=O or C(H)OR wherein R is hydrogen or (lower)alkanoyl; Q is H, OH or OCOR wherein R is lower alkyl; Z is (lower)alkyl, the wavy line (i) designating alpha or beta configuration; and R is hydrogen or (lower) alkyl, provided that when wherein R is hydrogen or methyl, and provided that when 16- 1'zis X is other than Alkyl O More particularly, a second embodiment is contemplated which are steroid compounds of Formula I wherein X 1s wherein R is hydrogen or (lower)alkyl;

wherein R is hydrogen or (lower)alkanoyl; or

wherein R is hydrogen or methyl and -C C is a divalent l cm 15 cm D wherein D is chloro, bromo or fiuoro and D is chloro or bromo, the wavy line (3) designating alpha or beta configuration and the broken lines designating single or double bonds provided that when G is 0:0, Q is H and Z is alpha, -C -C is other than The term (lower)alkyl includes hydrocarbon chains of from about 1 to about -6 carbon atoms, both straight chain and branched, illustrative members of which are methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like. The term polycarbon alkyl contemplates polycarbon(lower)alkyl, containing from about 2 to about 6 carbon atoms and includes groups illustrated above but excluding the methyl group; the ethyl group is preferred. The term (lower)- alkanoyl contemplates groups of the formula (lower)- alkylCO-, wherein (lower)alkyl is above defined, and the formyl group.

With reference to compounds of Formula I, acetyl is a preferred (lower)alkanoyl group. The term D-homo" refers to a steroid structure wherein the D-ring comprises 6 carbon atoms (i.e., a is 2) in contrast to the normal series of steroid compounds wherein, the D-ring comprises carbon atoms (a is 1). The term (lower) alkoxy includes straight and branched chain groups of from about 1 to about 6 carbon atoms, such as methoXy, ethoxy, n-propoxy, i-propoxy, n-hexoxy and the like.

Special mention is made of a number of valuable embodiments of the instant invention. These are: 3rd, an

embodiment of the second, which are compounds of Formula Ia:

wherein R is polycarb0n(lower) alkyl of from about 2 to about 6 carbon atoms; Q is H, OH or OCOR wherein R is lower alkyl; Z is (l0wer)alkyl; and C -C is a divalent radical of the formulae:

wherein D is chloro, bromo or fluoro and D is chloro or bromo, the wavy lines designating alpha or beta configuration, provided that when Q is H and Z is alpha, -C C is other than Special mention is made of a number of valuable embodiments embraced by Formula Ia. These are:

4th, 17fl-acetyl-l3-ethyl-16l8-methylgon-4-en-3-one;

6th, 17,8-acetyl-13-ethyl-17a-hydroxy-l6a-methylgon-4- en-3-one;

7th, 17,8-acetyl-13-ethyl-17u-hydroxy-l6fl-methylgon-4 en-3-one;

8th, 17/8-acetyl-13-ethy1-l7u-hydroxy-16a-methylgon-4- en-3-one, acetate;

9th, 17B-acetyl-l3-ethyl-17a-hydroxy-16,3-methylgon-4- en-3-one, acetate;

10th, 17 3-acetyl-17a-acetoxy-13-ethyl-16a-methylgona- 4,6-dien-3-one;

11th, 17p-acetyl-l7a-acetoxy-l3-ethyl-16B-methylgona- 4,6-dien-3-one;

12th, 17,8-acetyl-17u-acetoxy-6-chloro-l3-ethyl-16umethylgona-4,6-dien-3-one; and

13th, 17/3-acetyl-17a-acetoxy-6-chloro-13-ethyl-1'6flmethylgona-4,6-dien-3-one.

Also illustrative of valuable compounds embraced by Formula Ia are:

17 B-acetyl-13-ethyl-6B-16a-dimethylgon-4-en-3-one; 17,B-acetyl-13-ethyl-6/3,16,8-dimethylgon-4-en-3-one; l7/3-acetyl-6a-chloro-13-ethyl-16u-methylgon-4-en-3-one; 17B-acetyl-6wchloro-13-ethyl-16fl-methylgon-4-en-3-one; and the like.

Illustrative of valuable compounds provided by the processes of the instant invention are 17,3-acetyl-13-ethyl- 16a-methylgon-4-en-3-one and 17/3-acetyl-6a,16a-di methyl-13-ethylgon-4-en-3-one.

The compounds of Formula I herein are valuable hormonally-active substances and intermediates for hormonally-active substances. Compounds of Formula Ia have been found to be active in standard pharmacological tests in laboratory animals, such as mice, rats, rabbits and the like, progestationally and anti estrogenically. They are more active then many known compounds now used with these activities and, in addition, possess a valuable separation of hormonal properties to a greater degree than compounds presently used with these activities. Particularly valuable are compounds of the 4th through 13th embodiments. Progestationally-active substances are used in cases of infertility and more specifically, but without limitation, to delay estrus and ovulation in cattle, pigs and dogs. Anti-estrogenically-active compounds are administered to counter the effects due to an excess of estrogen, such as estrone and similar metrotropic agents. The instant compounds are also of value in that field of use known as microdose contraception. They have an anti-fertility effect at considerably lower levels of administration than the levels used conventionally, e.g., 1 mg. to 100 mg., on a daily basis.

This invention also contemplates as a 14th embodiment steroid compounds of Formula Ib:

C n X 2 n In wherein R is polycarbon(lower)alkyl; n is 1 or 2, -C C is a divalent radical of the formulae:

wherein Y is hydrogen or --CH R wherein R is hydrogen or (lower)alkyl; and R is hydrogen or (lower)alkyl; and X is COCH wherein R is hydrogen or (lower)alkyl;

wherein R is hydrogen or (lower) alkanoyl; or

wherein R is hydrogen or methyl and -C -C is a divalent radical of the formulae:

E l I 17th, 17-acetyl-13-ethylgona-4,16-dien-3-one;

18th, 17-acetyl-13-ethyl-3-methoxy-16-methylgona-1,3, ,16-tetraene;

19th, 17-acetyl l3-ethylgona-5,l6-dien-35-ol, acetate and its free 35-01; and

20th, 17-acetyl 13 ethyl 16 L methylgona-5,16-dien- 35-01, acetate and its free 3501.

Also contemplated as embodiments of the second are the 21st, 175 acetyl 13 ethyl--methylgon-5-en-35-ol, acetate;

22nd, acetyl 13 ethyl-16a-methylgon-5-ene-35, 17a-diol;

23rd, 175 acetyl 13 ethyl-l6a-methy1gona-3,5-diene- 3,17a-di0l;

24th, 13 ethyl 175 (l-hydroxyethyl)-16a-methyl-3- methoxygona- 1,3,5( 10) -trien- 1711-01; and

25th, 13 ethyl 175 (l-hydroxyethyl)-17a-hydroxy- 16a-methylgon-4-en-3-one.

This invention also contemplates as a 26th embodiment, compounds of Formula Ic:

Insert 855 A wherein R is polycarbon (lower) alkyl; Q is H, OH or OCOR wherein R is lower alkyl; Z is (1ower)alkyl; and R is hydrogen or (lower)alkyl, the wavy line (i) designating alpha or beta configuration.

Special mention is made of a number of valuable embodiments within the scope of Formula Ic. These are:

27th, 17 5 acetyl 13-ethyl-16-methyl-3-methoxygona- 1,3,5 (10)-trien or the 16u-epimer thereof;

28th, 175 acetyl 13 ethyl 16oz methyl-S-methoxygona- 1,3,5 10) -trien-17a-ol; and

29th, 175 acetyl 13 ethyl 165 methyl-S-methoxygona-1,3,5 10) -trien-17a-ol.

The compounds of Formulae Ib and lo herein are valuable hormonally-active substances. They have been found to be active in standard pharmacological tests in laboratory animals such as mice, rats and the like, estrogenically and anti-lipemically. Particularly valuable are the compounds of the 15th through 23rd and the 27th through 29th embodiments. Estrogenically active substances are used to treat the symptoms of estrogen deficiencies, such as to induce heat in anestrus. Anti-lipemically active compounds are administered to curb a tendency to develop atherosclerosis. In addition, and as will be demonstrated hereinafter, compounds of Formula I are especially valuable as intermediates in the synthesis of hormonally active steroids, such as progesterone, and in particular, other compounds having progestational and anti-estrogenic activity.

In another broad aspect, the present invention contemplates, as a 30th embodiment; a process for the preparation of a compound of the 17-acetylgon-16-ene series or a D-homo analog thereof, which comprises heating a solution of the corresponding 17-ethynylgon-16-ene or D-homo analog thereof in the presence of water and a catalyst until hydration of the l7-ethynyl group is substantially complete, and recovering said acetyl compound. This aspect can be'depicted as follows:

CEO R H R OOCH: 'iHrO i x Hr). X z).

Ha Id wherein R is (lower)a1kyl and X and n are as above defined. The compound of Formula I Ia can be dissolved or suspended in a mixture of a (lower) alkanol, such as ethanol or methanol, and water, then a hydration promoter or catalyst, e.g., a mercurated cation exchange resin, is added and the reaction mixture can be heated above about 50 C. and preferably to refluxing until hydration is sub stantially complete, e.g., from about 1 to about 24 hours-- usually 5 hours is adequate. The product (Id) is recovered, for example, by filtering the reaction mixture and adding enough water to cause complete separation of the product. If desired it can be purified by recrystallization from a (lower) alkanol. Alternately, the catalyst can be a heavy metal ion salt, derived from, for example, silver, mercury and the like and in this case refluxing aqueous dioxane or tetrahydrofuran solvent systems are very useful.

As variants of this 30th embodiment there are mentioned: a 31st embodiment, wherein the catalyst in said process is a mercurated cation exchange resin, generally of the sulfonated, cross-linked polystyrene type described, for example, in US. Pat. 2,366,007, or an obvious chemical equivalent thereof, of about a 200-400 mesh-size, preferably one which has first been treated with a strong mineral acid, such as sulfuric acid or hydrochloric acid, for conversion to the hydrogen ion form, and then activated by treatment with a soluble mercuric salt, such as mercuric acetate, or an obvious chemical equivalent thereof, until formation of the mercurated cation exchange resin was complete;

A 32nd embodiment, which is the process of the 30th embodiment including the step of preparing said 17-ethynylgon-16-ene or D-homo analog thereof by dehydrating a corresponding 17a ethynylgonan-l7u-ol or D-homo analog thereof. This aspect can be depicted as follows:

on 05011 R "CECE R -H,o m X H91: x oHz)..

III Ha wherein R is (lower)alkyl and X and n are as above defined. Dehydration if III can be carried out conveniently by heating in a solvent in the presence of a water-removal agent. In one manner of proceeding, III is added to a cold, e.g., C., mixture of pyridine and excess phosphorus oxychloride. The reaction is promoted by heating to about 90-100 C.; usually about 30 minutes is adequate. 11a is recovered, for example, by pouring the reaction mixture into water or aqueous acid and separating the solid. IIa can be purified, if desired, by recrystallization from a (lower)alkanol, e.g., methanol or isopropanol;

A 33rd embodiment, which is the process of the 32nd embodiment wherein the dehydration is accomplished by treatment with phosphorus oxychloride in pyridine or an obvious equivalent thereof;

A 34th embodiment, which is a process for the preparation of a compound of the 17a-acetyl gonan-l7p3-ol, formate or (lower)alkanoate (particularly acetate) series or a D-homo analog thereof which comprises heating an alcoholic solution of the corresponding 17a ethyynylgonan-17 3-ol, formate or alkanoate, or D-homo analog thereof in the presence of water and a catalyst until hydration of the 17a-ethynyl group is substantially complete, and recovering said compound; this aspect can be depicted as follows:

3 a con R con R CCll cocu +11 0 it X an 11s Ie wherein R is (lower)alkyl and R X and n are as above defined; the hydration of IIb to Ie is carried out generally by the same procedure outlined above to hydrate 11a to Id. Ie can be purified by the techniques described for Ia and it can also be purified by chromatography, for example, in benzene on a column of fluorosilicate;

A 35th embodiment which is the process of the 34th embodiment wherein the catalyst is a mercurated cation exchange resin of the type described in the 31st embodiment;

A 36th embodiment which is the process of the 34th wherein said catalyst is silver nitrate; and

A 37th embodiment which is the process of the 34th embodiment including the step of preparing said ethynylgonan-17fi-ol, formate, or D-homo analog thereof, by reacting the corresponding 17a-ethyny1gonan-17p-ol, or D-homo analog thereof with dimethylformamide in the presence of phosphorous oxychloride; this aspect can be depicted as follows:

on R OCHO R c.=.cn

our POCl x (CH a x (c11 III IIc wherein R is (lower)alkyl and X and n are as above defined and DMF is dimethylformamide. The formylation of III occurs smoothly in a mixture of dimethylformamide and phosphorus oxychloride. The dimethyl formamide is cooled to about 05 C. and about A: volume of POCl is added, then compound III. After only a short time, about 3 minutes, formylation is complete and the product He is recovered, for example, by pouring the reaction mixture into a cold solution of pyridine and water which causes it to precipitate. He can be purified if desired by recrystallization from a lower alkanol, such as isopropanol. The corresponding (lower)alkanoates, i.e., R is (lower)alkyl are prepared by reaction of III with the corresponding alkanoyl halide or anhydride in a solvent such as ethyl acetate with catalytic pyridine.

Also contemplated by this invention is a 38th embodiment which is a process for the preparation of a compound of the 17/8-acetylgonane series, or a D-homo analog thereof, which comprises:

(a) Reducing a compound of the 17-acetylgon-16-ene series of a D-homo analog thereof; or

(b) Reductively cleaving a compound of the 170:- acetylgonan-17 3-ol, formate or alkanoate series or a D- homo analog thereof (Ie), provided that Ie does not contain a conjugated ketone or other art-recognized moiety subject to side reactions, until formation of said acetylgonane or D-homo analog is substantially complete, and recovering said reduced compound. This embodiment provides one means to obtain the valuable hormonally active steroids using the instant compounds of Formula I as intermediates. It can be depicted as follows:

ocoR

COCli COCH wherein R is (lower) alkyl and R X and n are as herein above defined. To carry out step (a) a mixture of a catalyst, such as 5 or 10% palladium on carbon and ethanol is pretreated with hydrogen; a solution of Id in a solvent such as ethyl acetate is added and hydrogen is admitted until the uptake is complete. IV is recovered by filtering of the catalyst and evaporating oif the solvent. The residue (IV) can be purified by recrystallization, e.g., from acetone, hexane or mixtures thereof. To carry out (b), Ie is cleaved with an alkali metal, e.g., potassium, sodium or lithium (or an alkaline earth metal, e.g., calcium, in a liquid amine, e.g., ammonia. A solution of Ie in a solvent such as dioxane, tetrahydrofuran, ether and the like, can be added to a solution of calcium in liquid ammonia. After reaction is complete, about 1 hour, the mixture is quenched, e.g., with NH CI and the product is thrown down by adding Water. It can be purified by recrystallization, as above.

As variants there are contemplated: a 39th embodiment which is the process of the 38th wherein, in alternative (a), the reduction is carried out with hydrogen in the presence of a catalyst, preferably a noble metal catalyst, such as a platinum or a palladium catalyst, or with an alkali metal, such as sodium or lithium, or an alkaline earth metal, such as calcium, in a liquid amine, such as ammonia and preferably in the presence of an alkanol, such as t-butyl alcohol, and, in alternative (b) the reductive cleavage is carried out with an alkali metal, such as sodium or lithium, or an alkaline earth metal, such as calcium, in a liquid amine, such as ammonia and preferably in the presence of an alkanol, such as t-butyl alcohol;

A 40th embodiment which is the process of the 38th wherein the very valuable hormone progesterone is prepared by reducing 17-acetyl-l0,13-dimethylgon-4,16-dien- 3-one; this can be depicted as follows:

COCll W k NJ EIOCll IVa cocu

on 0 W11 10 wherein R is hydrogen or methyl and wherein compound IVb is 17,8 acetyl-13-ethyl-3-methoxygona-1,3, 5(10)-triene;

A 42nd embodiment of this invention is a process for the preparation of a compound of the 17,8-acetylgon-4- en-S-one series, or a D-homo analog thereof, which comprises:

(a)(i) Reducing the corresponding 17 acetyl-3-alkoXygona-l,3,5(10), 16-tetraene or (ii) cleaving and reducing the corresponding a acetyl-3-alkoxygona-L3, 5(l0)-trien-17,8-ol, formate or alkanoate, until formation of the corresponding 17B (a-hydroxyethyl)-3-alk- 0xygona-2,5(l0)-diene is substantially complete;

(b) Hydrolyzing said gona-2,5-(l0)-diene from step (a) with acid until formation of the corresponding 17B- (a-hydroxyethyl) gon-4-en-3-one is substantially complete; and

(c) Oxidizing said gon-4-en-3-one from step (b) until formation of said 17fi-acetylgon-4-en-3-one is substantially complete. This can be depicted as follows:

IVc

wherein R is (lower)alkyl, preferably polycarbon (lower) alkyl and R is (lower)alkyl and R and n are as hereinabove defined. In one manner of proceeding, Ii or Ij in a solvent such as dioxane can be added to a solution of lithium in distilled liquid ammonia and then the mixture is stirred for about an hour. t-Butanol is added, the mixture is stirred a further hour, more lithium is added and the mixture is stirred a final hour. V can be recovered by adding methanol to discharge the blue color and not water to boil 01f the ammonia. V can be converted to VI by dissolving in boiling alcohol, e.g., methanol containing mineral acid, e. g., hydrochloric acid and boiling for about an hour. VI is recovered by adding excess water, extracting, e.g., with ether and evaporating the solvent. VI is converted to IVc by Jones oxidation, e.g., by solution in acetone, adding sodium sulfate and then 8 N chromic acid. After about /2 hour, water is added to precipitate We and it is purified by chromatography in benzene over neutral alumina and by recrystallization, e.g., from acetone, hexane or mixtures thereof;

A 43rd embodiment is the process as defined under the 42nd above wherein step (a) (i) or (ii), is carried out in the presence of excess lithium in liquid ammonia and tbutanol; step (b) is carried out in methanol and hydrochloric acid; and the oxidation in step (c) is carried out with 8 N chromic acid in anhydrous acetone;

A 44th embodiment is the process as defined under the 42nd above wherein 17/3-acetyl-13-ethylgon-4-en-3-one is prepared by (a) (i) Reducing 17 acetyl 13-ethyl-3-methoxygon- 1,3,5(l),16-tetraene or (ii) cleaving and reducing 17aacetyl l3 ethyl 3 methoxygona-1,3,5(l0)-triene- 1713-01, formate or acetate to form 17B-(ot-hydroxyethyl)- 13-ethyl-3-methoxygona-2,5 -diene:

(b) Hydrolyzing the product of step (a) to provide 17/8-(a-hydroxyethyl) 13 ethylgon-4-en-3-onc; and

(c) Oxidizing the product of step (b) to provide said 17 B-acetyl- 1 3-ethylgon-4-en-3 -one.

This valuable embodiment is depicted by the pathway under the 41st above wherein R is ethyl and n is 1. The product, 17,8 acetyl 13-ethylgon-4-en-3-one, is an important, known progestational agent.

The valuable product of the 44th embodiment is also provided by the 45th embodiment which is a process as defined under the 38th above wherein 17fl-acetyl-13-ethylgon-4-en-3-one is prepared by reducing 17-acety1-13-ethylgona-4,l6-dien-3-one; this selective reduction can be accomplished, for example, by hydrogenation in the presence of a catalyst, preferably a noble metal catalyst, e.g., 5% palladium on charcoal, and can be depicted in the following way:

cocucocu (lower) alkyl Mg -hal wherein hal is bromo, iodo or chloro and (lower)alkyl is as above defined and preferably methyl, until formation of the corresponding l7-acetyl-16a-(lower)alkylgonane enolate is substantially complete, reacting said enolate with acid and recovering said gonane; this can be depicted as follows:

COCli cocn wherein R is (lower)alkyl and X, Z, n and hal are as above defined. A 3 M ethereal solution of Grignard reagent, e.g., methyl magnesium iodide, can be diluted with 5 volumes of solvent, e.g., diethyl ether and a promotor, cuprous chloride, can be added. Then a suspension of Id in ether is added and the mixture is refluxed until formation of the Grignard complex is complete-about 2 hours. The mixture is cooled and quenched with NH Cl, filtered washed and dried. Evaporation of the solvents leaves VII as a residue, which can be purified by chromatography in benzene on neutral alumina or by recrystallization from a lower alkanol, e.g., ethanol;

The 47th embodiment which is a process as defined under the 46th wherein 17-acetyl-l3-ethylgona-4,16-dien- 3-one is reacted with excess methyl magnesium iodide then treated with acid to provide l7B-acetyl-13-ethyl-5fl, 16a-dimethylgon-3-one; this can be depicted as follows:

Cocu we":

12 The product of this embodiment, 17B-acetyl-13-ethyl-55, 16a-dimethylgon-3-one (Vila) is hormonally active as an anti-androgenic agent with anti-estrogenic activity;

The 48th embodiment which is a process as defined under the 46th above wherein 17-acety1-l3-ethyl-3-methoxygona-1,3,5(10),16-tetraene is reacted with methyl magnesium iodide to provide 17fi-acetyl-13-ethyl-6a-methyl-3-methoxygona-l,3,5(10)-triene. This embodiment can be depicted as follows:

cocir coon +11 0 9 --cn (1) cu NgI c 'J'fi a (2) "s on o VIII:

Ii. V111) wherein R is (lower)alkyl, preferably polycarbon(lower) alkyl and R is hydrogen or (lower)alkyl, Z is (lower) alkyl and n is 1 or 2; the general procedure to go from Ij t0 IVc outlined above is also useful to proceed from VIIb to X; and a 50th embodiment which is the process of the 49th wherein 17fi-acetyl-1S-ethyl-l6a-methylgon-4-en-3-one is prepared by:

(a) Reducing 17fi-acetyl-13-ethyl-16ot-methyl 3 methoxygona-1,3,5(l0)-triene to form 17fi-(a-hydroxyethyl l 3-ethyl-5-methoxyl 6a-methylgona-2,5 10 -diene;

(b)Treating the product of step (a) with an acid to provide 17p-(a-hydroxyethyl)-13-ethyl-16wmethylgon-4- en-3-one; and

(c) Oxidizing the product of step (a) with an acid to provide acetyl-13-ethyl-16a-methylgon-4-en-3-one; this aspect may be depicted as outlined under the 49th above wherein R is ethyl and n is 1. The product of this embodiment, 17B-acetyl-13-ethyl-16u-methylgon-4-en-3-one has especially valuable progestational properties.

A further aspect of the instant invention is the 51st embodiment, which is a process as defined in the 46th above including the steps of (a) Treating first with an epoxidizing agent and then with a base a 17-(l-lower)alkanoyloxyethylidene) -3- alkoxy-l 61x- (lower) alkylgona-1,3,5 10 -triene until formation of the corresponding 17B-acetyl-3-alkoxy-16a- (lower) alkylgona-1,3,5 10)-trien-17u-ol is substantially complete;

(b) Reducing the product from step (a) until formation of a 17/3-(I-hydroxyethyl)-3-alkoxy-16a-(lower) alkylgona-1,3,5(10)-trien-17ot-ol is substantially complete;

Reducing the product of step (b) under Birch conditions, e.g., as by treatment with lithium and liquid ammonia in THF in the presence of l-methoxy-Z-propanol, then with ammonium chloride, until formation of the corresponding 175 (l-hydroxyethyl)-4-alkoXy-16u-(lower) alkylgona-2,5 ()-di6Il-17OL-O1 is substantially complete;

(d) Hydrolyzing the product from step (c) with acid, e.g., hydrochloric acid, until formation of the corresponding 17pl-hydroxyethyl) -17a-hydroxy-1 6a- (lower) alkylgon-4-en-3-one is substantially complete; and

(e) Oxidizing, e.g., with acetic anhydride and dimethylsulfoxide, the product of step (d) until formation of a 175 acetyl-17ot-hydroxy-16u-(lower)alkylgon-4-en-3-one is substantially complete.

As aspect of this is the 52nd embodiment, which is the process of the 51st wherein 17,6-acetyl-13-ethyl-16u-meth ylgon-4-en-3-on-17a-ol is prepared by:

(a) Epoxidizing and hydrolyzing 13-ethyl-17(1-acetoxyethylidene) 16oz methyl-3-methoxygona-1,3,5(10)- triene to form 17B-acetyl-13-ethyl-l6m-methyl-3-methoxygona-1,3,5 l0)-trien-17a-ol;

(b) Treating the product of step (a) with a reducing agent to form 13-ethyl-17fi-(1-hydroxyethyl)-l6a-methyl- 3-methoXygano-1,3,5-( 10 -trien- 1706-01;

(c) Reducing the product from step (b) to form 13- ethyl 175-(1-hydroxyethyl)-16a-methyl-3-methoxygona- 2,5 10)-dien-17u-ol;

(d) Hydrolyzing the product from step (c) with an acid to form 13-ethyl-17;8-(l-hydroxyethyl)-17a-hydroXy- 16a-methylgon-4-en-3-one; and

(e) Oxidizing the product of step (d) to form 17 8- ace tyl- 1 3 -ethyl- 17a-hydroxy-1 6a-methylgon-4en-3 -one.

Other valuable products are provided by the 53rd embodiment which is a process as defined in the 51st including the steps of (a) Enolalkanoylating the product until formation of the corresponding 17p acetyl 16a (lower)alkylgona- 3,5 diene 3,170: diol, di(lower)alkanoate is substantially complete; and

(b) Hydrolyzing the product of step (a) until formation of the corresponding 17fi-acetyl 17o: hydroxy-16amethylgon 4 en 3 one, (lower)alkanoate is substantially complete.

An aspect of this is the 54th embodiment which is a process as defined in the 53rd wherein 17B-acetyl-13-ethyl- 17cc hydroxy-16a-methylgon-4-en-3-one, acetate, is prepared by:

(a) Enolacetylating 17B acetyl 13 ethyl 17cc hydroxy 16m methylgon-4-en-3-one to form 17B-acetyl- 13-ethyl 16a methylgona 3,5 diene 3,17 diol,

diacetate; and

(b) Hydrolyzing the product of step (a) to form 175- acetyl 13 ethyl 17a hydroxy 16a methylgon-4- en-3-one, acetate.

The aspects of the 51st to 54th embodiments can be depicted as follows:

3 COCH (E-OCOCH 6W CH O (2)CH CQCJ. CH 0 (1) m-ch-lcroperbenzoic acid (2) base CH COCH iIHOH OH H CH3 CH 5 CH 0 CH 0 NaBH 3 l/i/1m (Birch rcd'n (3H CH0 DMBO court cocn --ococn CH Perchloric ii mild. acid base i s hydrolys s "P 9 3 V cs wherein Ac O is acetic anhydride and DMSO is dimethyl sulfoxide. These procedures will be exemplified in detail hereinafter.

A further aspect of the instant invention is the 55th embodiment, which is a process as defined in the 32nd above wherein (a) 13-ethyl 17oz ethynyl 3 methoxy 16,3 methylgona 1,3,5(10) trien-17B-ol is dehydrated to produce 13-ethyl 17 ethynyl 3 methoxy 16 methylgona- 1,3,5(10),16-tetraene; and including the steps of (b) Heating said ethynyltetraene in solution with water and a catalyst to produce 17-acetyl 13 ethyl-3- methoxyl-methylgona- 1,3,5 10),16-tetraene; and

(c) Catalytically hydrogenating said acetyltetraene to form 17p-acetyl 13 ethyl-3-methoxy-16B-methylgona- 1,3,5(10)-triene. The preparation of the substrate used in step (a) is described in detail hereinafter. Reaction conditions useful to accomplish the reactions of steps (a), (b) and (c) are described in the disclosure of the 32nd, 30th and 38th embodiments, respectively, hereinabove.

This aspect can be depicted as follows:

COCll' CUCII R 3 x1 wherein R is (lower)alkyl, X and n are as defined hereinabove, diazoalkane is a diazo(lower)alkane compound such as diazomethane or diazoethane or an obvious chemical equivalent thereof, and R is hydrogen or (lower)alkyl; Compound Id can be added as an ethereal solution to the diazoalkane, generated in situ by the standard procedures, e.g., by treating N-nitrosornethylurea with base (for diazomethane). The reaction proceeds to completion at moderate temperatures, e.g. 1540 C. in several hours; even up to 24 hours is entirely satisfactory. XI is recovered by mixing the mixture with water and gently boiling off the ether. The product is filtered off and can be recrystallized from a lower alkanol, e.g., ethanol. Heating XI converts it to I1. For example, add XI to diethylene glycol at about -200, preferably C. and heat about an hour. Cool, add excess water to throw down 11, filter off and, if desired, crystallize II from a (lower) alkanol, e.g., methanol. XI can if desired merely be heated above its melting point (without a solvent) to provide 11.

A 57th embodiment is a process as defined under the 5 6th wherein the diazoalkane in step (a) is diazomethane. This provides the instant compounds of Formula II wherein R is hydrogen (e.g., 16-methyl compounds) which, in addition to their valuable estrogenic and anti-lipemic properties, serve as valuable precursors for the entire series of l7B-acetyl-l6B-methylgonanes and l7u-oxygenated-l7/3- acetyl-l6fl-methylgonanes as will be shown hereinafter; and a 58th embodiment is the process of the 56th where- COClI .COGI

\ cow The valuable objects of this invention are also secured by the 59th embodiment which is the process of the 56th including the step of catalytically hydrogenating said 17- acetyl-l6-alkylgon-16-cne until formation of the corresponding 17-acetyl-16-alkylgonane is substantially complete. This is represented schematically as follows:

R coon cocu R 4 {jg cu R Z ll (cu) 2 9 X 2 n catalyst X I]. In.

wherein R, R X, Z and n are as hereinabove defined. The conditions of hydrogenation and the catalyst can generally be derived from those described in going from Id to IV in the 38th embodiment;

The 60th embodiment which is the process of the 59th wherein 17-acetyl-13-ethyl-3-methoxy-l6-methylgona-1,3, 5 (l0),l6-tetraene is catalytically hydrogenated to provide 17fl-acetyl-13-ethyl-3-methoxy-l6fl methylgona 1,3,5 (10)-triene;

The 61st embodiment which is the process of the 59th including the steps of:

(a) Reducing a l7f3-acetyl-l6-(lower)alkylgona-l,3,5- (lO)-triene until formation of the corresponding l7fl-(othydroxyethyl)gona-2,5(10)-diene is substantially complete;

(b) Hydrolyzing said gona-2,5(10)-diene from step (a) with acid until formation of the corresponding l7fl-(a-hydroxyethyl)-gon-4-en-3-one is substantially complete; and

(c) Oxidizing said gon-4-en-3-one from step (13) until formation of a 17 3-acetyl-l6-(lower)alkylgon-4-en-3-onc is substantially completed. This is depicted in the pathway from VIIb to X, above, except that Z will have the beta configuration; and

A 62nd embodiment which is the process of the 61st wherein 17/3-acetyl-13-ethyl-16B-methylgon-4-en-3-one is prepared by:

(a) Reducing l7B-acetyl-l3-ethyl-3 methoxy 16 3- methylgona-1,3,5(10)-triene to form 17B-(ot-hydroxyethyl) l 3-ethy1-3-methoxy- 16B-methylgona-2,5( 10) -diene;

(b) Treating the product of step (a) with acid to form 17/3-(u-hydroxyethyl)-l3-ethy1-16p-methylgona 4 en 3- one; and

(c) Oxidizing the product of step (b) to provide 17B- acetyl-13-ethyl-16fi-methylgon-4-en-3-one.

The processes outlined hereinabove provide compounds of Formula I wherein R, n, X, Y, Z and R are as 1st hereinabove defined, G is C=O or C(H)OR wherein R is hydrogen and Q is H. To prepare those wherein R is (lower)alkanoyl it is merely necessary to react the corresponding 20-01, e.g., IX, with an alkanoylating agent, such as an alkanoyl halide e.g., acetyl chloride or an anhydride, such as acetic anhydride, in a solvent, such as ethyl acetate in the presence of catalytic pyridine, according to well known procedures.

Introduction of the 170t-Sl1bStltlJ6l1tS and of substituents at C and of double bonds at various positions can be accomplished according to one or more of the following pathways: 7

(a) The 16a-(lower)alkyl compounds are prepared as follows:

wherein R is (lwer)alkyl, preferably polycarbon (lower) alkyl, R R and Z are .(1ower)alkyl, n is 1 or 2 and R is (lower)alkyl. This procedure will be exemplified in detail hereinafter. 5 Alternatively, as is shown, Ii can be converted to Io in one operation by introducing the l6a-(lower)alkyl group and a 17u-hydroxy function with (lower)alkyl magnesium halide (step Ia) followed by bubbling oxygen gas into the mixture, then the Grignard complex is decomposed. The operation also is especially useful to convert the corresponding 17 acetyl-13-alkyl-3-(lower)alkoxygona-1,3,5(l0),16-tetraene to the instant l7,B-acetyl-l3- alkyl-la-(lower) alkyl-3-(lower) alkoxygona 1,3,5()- tetraenes. These procedures will be exemplified in detail hereinafter.

(b) Similarly, the 16 3-(lower)alkyl compounds are prepared as follows:

R coon R -ocon 7m. chlofi c H2) tl i 0 1y 5 .acctate IS XIIb in (1) perncid Tnuon R s (2) KOlI/MeOH on l}o R \o i 11001 611 09: g It benzene (011 Ziiiii'ficid 5 MW: R 0

5 l/ coca R 0 R t-lluOlI 2* Li/Nli z XIVb wi HE) MCI/M001! R5 11 0 9 m In cocu CO '1 R 3 R C o tr-o 0 per-chlor de ncid, y, R 0C0R2 ,[u Z

tl 1 y 0 M "B n M0 0 9 2 Moon u oco o Iv I" wherein R is (lower)alkyl, preferably polycarbon (lower)alkyl, R and Z are (lower)alkyl, n is 1 or 2, R is hydrogen or (lower)alkyl and R is (lower)alkyl. This procedure will be exemplified in detail hereinafter.

19 (c) Alternatively, the 16a-(lower)alkyl compounds of Formula Ip can be prepared proceeding through a valuable new intermediate of Formula Ix, as follows:

Since some free 36-01 is formed in the hydration reaction to produce IX, it is best handled by completing the hydrolysis in a separate operation to obtain Ix. Alternatively, Ix is converted via XIIc and XIIIb to Iy, as follows:

() (lower al kyl Mg hal Ix XIIc Cu Cl 8 (2) R CO hal q 8 1 mole perncid COG" l ocoR 3 ll R Z -Clll Lil 8 KOll/MoOll R 0L0 no y Oppcmmcl' oxidation wherein R is (lower)alkyl, preferably polycarbon (lower)alkyl, R and R and Z are (lower)alkyl and n is 1 or 2 (d) On the other hand, treatment of the enol acetate XIIc with 2 moles of peracid will lead into the series of 6fl-methyl analogs of Ip, namely compounds of Formula Ibb:

2 moles of permit! hOll/HoOll "0 CH3 (1) Nnurr l (a) NcMgI/Ethcr/rcflux n uou --Oll Oppcnauc oxidation no I wherein R, R and Z are (loweralkvl and n is 1 or 2.

(e) Similarly, the 16fl-(lower)alkyl counterparts of Ip and Ibb, namely, compounds of Formulae Ice and Id are obtained by entirely analogous pathways from the (lower)alkyl enol ether of Formula XIId which is prepared, for example, from Ix, as follows:

wherein R is (lower)alkyl, preferably polycarbon (lower)alkyl, R, R and Z are (l0wer)alkyl and n is 1 or 2.

(f) The delta-4,6-dehydro and the 6-chloro, bromo and fluoro analogs within the scope of Formula I are accessible by the following pathway:

R h, coon COCII "2 nnhydr on s wherein R, R and Z are (lower)a1kyl, n is 1 or 2 and D is bromo or chloro, respectively.

(g) The 6-methyl-4-ones and 6-methyl-4,6-dienes of Formula I are accessible by the following pathway:

R JHOCOH UKQHIMeOIt H 2 )NaBli /llcoli T 5 on R Lam! n n p Inn hydrogen, catalyst 5 I R cnOH.

H an 7 0 chronic 0 acid in CH acetone 5 I I00 PP COCK.- E o I rearrange Inn Z with weak husc, mg, 2 n. Nmtc wherein R is (lower)alkyl, preferably polycarbon (lower) alkyl, R is hydrogen or (lower)alkyl, n is 1 or 2, Z is (lower)a1kyl and DMF is dimethylformamide.

Introduction of a double bond at -C -C is accomplished in standard ways, such as with selenium dioxide dehydrogenation of the corresponding 4-en-3-one. Introduction of a double bond at -C C also is accomplished by standard means, such as by treatment of a gona-2,5(l0)-diene, e.g., XIIIa with a weak acid, such as oxalic acid or acetic acid to form the corresponding gon-5(l0)-ene-3-one, and treating this with about 1 equivalent of bromine in pyridine then pouring the reaction mixture into water. The introduction of a methyl group into the Ill-position (R in Formula I) can be accomplished in known ways, such as by Michael addition of the elements of hydrogen cyanide to gon-5(l0)-en-4- ones, then ketalization, reduction to the imine, Wolff- Kishner reduction and acid hydrolysis as described by D. P. Strike, D. Herbst and H. Smith in J. Med. Chem., 10, 446 (1967) or through the Simmons-Smith methylenation of the gen-5(10) en-SB-ol described by R. Rees, D. P. Strike and H. Smith in J. Med. Chem., 10, 783 (1967).

Starting materials for all of the above-mentioned compounds, i.e., those for Formula III:

R OH

zen

III

wherein R, X and n are as above defined, are readily available or can be prepared by techniques well known to those skilled in the art. A useful general means comprises reacting a suitably substituted 17-ketogonane, or D-homo analog thereof (after, of course, first protecting other reactive parts of the molecule, if present) with an ethynylating agent, such as a Grignard agent or an alkali metal acetylide. These means are described in detail together with methods for the total synthesis of compounds of Formula III by Douglas, Graves, Hartley, Hughes, McLaughlin, Siddall and Smith in J. Chem. Soc., 1963,

5072-5094; and by H. Smith, lHughes, Douglas, Wendt, Buzby, Jr., Edgren, Fisher, Foell, Gadsby, Hartley, Herbst, Jansen, Ledig, McLoughlin, McMenamin, Pattison, Phillips, Rees, Siddall, Suida, L. Smith, Tokolics, and Watson in J. Chem. Soc., 1964, 4472-4492.

The time and temperature ranges used in carrying out the above mentioned processes are not particularly critical and, as will be readily apparent to those skilled in the art, will 'be selected to carry out the reaction to a minimum of time without undue difficulty. Thus, reaction temperatures below those exemplified can be used, but then the reaction time is extended. On the other hand, reaction temperatures higher than those exemplified can be used with a concomitant decrease in reaction time, although purity of the product may be somewhat decreased.

In the product of a total synthesis which has not included a suitable resolution stage the compounds of the invention will be present as racemates. Using a convention approved by Fieser and Fieser, Steroids, p. 336 (1959), the compounds designated as the d-forms are the enantiomers corresponding in configuration at C-l3 to that of the natural hormone estrone. The corresponding enantiomorphs are consequently designated the l-forms and the racemates the a'l-forms. Racemates will be depicted by structural formulas which show only the enantiomorphs of the d-configuration.

As is mentioned hereinabove, the compounds of Formulae Ib and Ic of this invention have estrogenic and anti-lipemic activity. This makes them useful to treat conditions in animals, such as valuable domestic animals, and in laboratory animals, such as rats, mice and the like, responsive to treatment with estrogenic agents, such as the need to counteract estrogen deficiencies, and to overcome anestrus. In addition they are useful to lower the blood lipid level of animals and can be used wherever antilipemic agents are indicated, such as in the treatment of various hyperlipaemias or where the incidence of atherosclerosis is to be minimized. As is mentioned above, the products of Formula I are also useful as intermediates for the preparation of other steroids, such as progesterone, which have hormonal or other useful activities.

The products of Formula I of this invention can be used in association with a non-toxic carrier. They can be formulated in liquid or solid forms, for instance as capsules, tablets, suppositories, powders, dispensible granules, cachets, and the like by combining them with conventional carriers. Such conventional carrieE include magnesium carbonate or stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax and cocoa butter. Diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet-disintegrating agents can be used. Powders or tablets preferably contain 5 or to 99% of the active constituent. The active steroid can be formulated with an encapsulating material with or Without other carriers.

Liquid preparations such as solutions, suspensions or emulsions can also be used. Such preparations include dispersions in a non-toxic carrier such as arachis oil or sterile water, preferably containing a nonionic surface active agent such as fatty acid esters of polyhydroxy compounds, e.g., sorbitan, aqueous starch in sodium carboxymethyl cellulose solutions, aqueous propylene glycol or polyethylene glycol. Thus a water-propylene glycol solution can be used for parenteral injection and aqueous suspensions suitable for oral use can be made by utilizing natural or synthetic gums, resins, methyl cellulose or other well known suspending agents.

The composition can be in unit dose form in which the dose unit is for instance from about 0.1 to about 200 mg. of each active steroid. The unit dose form can be a packaged composition, e.g., packeted powder, vials, or ampules or, for example, in the form of capsules, cachets or tablets or any number of these in packaged form. The

pharmaceutical compositions can also consist substantially solely of the active steroid when this is in unit dose form. When used for the purposes stated above, the dosage of the compounds of Formula Ia will vary with the conditions being treated, but in general will be in the range established for progesterone (Merck Index, 7th ed., p. 856 (1960)). Moreover, when used for the purposes stated above, the dosage of the compounds of Formulae Ib and Ic will vary with the conditions being treated, but in general will be in the range established for estradiol (Merck Index, 7th ed., p. 416 (1960) I As valuable intermediates for compounds of Formula I this invention contemplates compounds. of Formulae XIb, XIIa, XlIb, XIIc, XIId, XIIIa, XIIIb, XIIIc, XIVa,

XIVb, XVa, XVb, as well as compounds of Formula VIIIb DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples are given by way of illustration and are not to be construed as limitations of this invention, variations of which are possible without departing from the scope and spirit thereof.

EXAMPLE '1 17-acetyl-l3-ethyl-3-methoxygona-1,3,5(l0) ,16-tetraene (a) dl-13-ethyl-17-ethynyl-3-meth0xygona 1,3,5 (10), l6-tetraene.-Cool pyridine (200 ml.) in an ice-bath then carefully add phosphorus oxychloride (30 ml.), stir and add dl-13-ethy1-17a-ethynyl 3 methoxygona-1,3,5(10)- trien-17 3-ol (10.0 g.) and heat the reaction mixture under nitrogen on a steam bath for 30 minutes. Cool the reaction mixture to about 23 C. then below by immersion in an ice-bath. Carefully pour the mixture into ice Water. Stir the mixture at room temperature with a little ether to induce crystallization. Blow off the ether (N and filter the resulting crystalline solid onto filter aid and air-dry the mixture. Extract the filter aid mixture with methylene chloride and filter. Reduce the methylene chloride to low volume in vacuo, treat the solution with decolorizing charcoal and filter'through filter aid. Remove the solevnt in vacuo, dissolve the resulting oil in hot methanol then allow to stand to complete crystallization. Filter to obtain 4.39 g. of the title product; M.P. 117120 C. Further purify a sample (1.30 g.) by dissolving in methylene chloride,- treating with decolorizing charcoal and filtering through filter aid. Remove the solvent in vacuo, dissolve the resulting oil in hot isopropanol, seed and let stand. Filter to obtain 0.96 g. of pure title product; M.P. l26-128 C.;

x52; 3.12 x53 226 m (6 15,600)

Analysis.-Calcd. for C H O (percent): C, 86.23; H, 8.55. Found (percent): C, 86.11; H, 8.52.

(b) a'l-'l7-acetyl-13-ethyl-3-methoxygona-l,3,5 (10),16- tetraene.-Prepared a sulfonated, polystyrene cross-linked cation exchange resin of 200-400 mesh to hydrate the ethynyl group by treating in the following manner: Mechanically stir a mixture of 1 lb. of the resin with a solution of 43ml. of concentrated sulfuric .acidin. 1600 ml. of water for 30 minutes.;Allow.to settle then decant the supernatant liquid from the resin. Wash the resin by treating with water and decanting as above three successive times with 1600 ml. each for 15- minutes each. Activate the resin by stirring for 30 minutes with a solution of mercuric acetate (5 g.) in 1660 ml. of water, decant, then wash four successive times with 1600 ml. of Water each time, as above: The resulting activated resin may be stored under water until use. Among the resins suitable for thispurpose is the product known as Arnberlite IR-120, marketed by Rohm and Haas, Philadel-' phia, Pa.

Filter 75 ml. of activated resin (prepared as above) and wash the filter cake with absolute ethanol. Place the resin along with water (10 ml.), absolute ethanol (200 ml.) and dl-l3-ethyl-17-ethynyl-3-methoxygona-1,3,5 10) 16-tetraene (3.00 g.) in a reaction flask and reflux the mixture for 5 hours. Filter the hot solution through filter aid. Wash the filter cake several times with hot ethanol. Obtain a separate filtrate by further washing the filter cake with methylene chloride. Dilute the ethanol filtrate with water and filter the resulting solid onto filter aid and air-dry the resulting mixture. Extract the filter aid mixture with methylene chloride and combine this filtrate with the methylene chloride filtrate obtained above. Remove the solvent in vacuo to obtain the title product as a yellow crystalline solid. Further purify the solid by dissolving in methylene chloride, treating with decolorizing charcoal and filtering through filter aid. Replace the methylene chloride with absolute ethanol by boiling on the steam-bath, seed and let stand to fully crystallize. Filter the resulting needles to obtain 2.30 g. of title product; M.P. 159-161 C. Obtain an analytical sample by treating 1.22 g. of the solid with decolorizing charcoal in methylene chloride as above to obtain from ethanol 1.02 g. of pure title product; M.P. 160 161.5 C.

A 6.06m A532? 228 m (6 11,400)

Analysis-Calm. for C H O (percent): C, 81.44; H, 8.70. Found (percent): C, 81.40; H, 8.68.

EXAMPLE 2 17 3-acetyl-12-ethyl-3-methoxygona-l,3,5 10)-triene Pre-treat a mixture of 5% palladium on carbon (300 mg.) and ethyl acetate (25 ml.) with hydrogen at atmospheric pressure. Add a solution of dl-17-acetyl-13-ethyl-3- methoxygona-1,3,5(),16-tetraene (0.80 g.) in ethyl acetate (150 ml.) and continue to react with hydrogen until uptake of the gas is complete. Filter the mixture through filter aid and remove the solvent in vacuo. Crystallize the resulting oil from methanol to get 0.63 g. of the title product; M.P. 123-125 C. Further purify the solid by dissolving it in methylene chloride, treating with decolorizing charcoal and filtering through filter aid. Remove the solvent in vacuo and crystallize the resulting oil from acetonehexane to obtain 0.45 g. of the pure title product as colorless prisms, M.P. 130133 C.;

A52; 5.9211 EXAMPLE 3 17fi-acetyl-13-ethylgon-4 en-one To a solution of lithium metal (1.00 g.) indistilled liquid ammonia (500 ml.) add a solution of dl-17-acetyl- 13-ethyl-3-methoxygona-1,3,5(10),16 tetraene (2.00 g.) in dry dioxane (50 ml.) and stir for 1 hour. Add t-butanol (100 ml.) dropwise to the stirred reaction mixture over a period of 1 hour, stir a further hour then add lithium metal (4.0 g.) and stir a final 1 hour. Add methanol dropwise until the blue color is discharged followed by warm water to boil ofr the ammonia. Filter the white solid onto filter aid, extract the filter cake with ether, filter and evaporate the ether in vacuo. Dissolve the resulting oil in boiling methanol (100 ml.) containing 4 N hydrochloric acid (30 ml.) and continue boiling for 45 minutes. Stir the cooled reaction at room temperature for 2 hours then add water (250 ml.) and extract with ether. Wash, dry and evaporate the extract in vacuo. Dissolve the resulting oil in acetone ml.) containing some anhydrous sodium sulfate then add 8 N chromic acid solution (5 ml.) dropwise and with stirring. Stir for 30 minutes more, then add water (200 ml.) and extract with ether. Wash, dry and evaporate the extract in vacuo. Filter the resulting oil in benzene through a short column of neutral, anhydrous alumina, evaporate the benzene in vacuo and crystallize the resulting colorless oil from acetone-hexane to get 0.69 g. of the pure title product, M.P. 141143 C.;

A521 5.90 and 6.02% A22} 238 mp. (e 16,800) EXAMPLE 4 17 a-acetyl- 13-ethyl-3-methoxygona-1,3,5 10) trien-17 3-ol, formate (a) dl-l3-ethyl-17a-ethynyl-3-methoxygona 1,3,5(10)- trien-l7 8-ol, formate.-Cool dimethylformamide (80 ml.) with an ice-bath, then under nitrogen add phosphorus oxychloride (12 ml.), stir, and add dl-l3-ethyl-17a-ethynyl- 3-methoxygona-1,3,5(10)-trien-17fi-ol (4.0 g.). Stir the cooled reaction for 3 minutes then pour it into an icecold solution of pyridine (75 ml.) in water (600 ml.). Stir to fully precipitate the product, filter onto filter aid, then extract the filter-cake with methylene chloride. Filter the extract, remove the solvent in vacuo and crystallize the residue from isopropanol to get 3.73 g. of the pure title product, M.P. 143-145 C.;

x55; 3.12, 4.77 and 5.83,.

Analysis.-Calcd. for C H O (percent): C, 78.37; H, 8.01. Found (percent): C, 78.72; H, 7.79.

(b) dl-l7a-acetyl 13 ethyl-3-methoxygona-1,3,5 (10)- trien-17B-ol, formate.Filter mercurated Amberlite IR- resin (200 ml. of resin which is activated by the procedure described in Example 1(b)), wash the resin with water and absolute ethanol, then mix it with water (100 ml.) in a reaction flask. Add a suspension of a l-13- ethyl-17u-ethynyl-3-methoxygona 1,3,5(10) trim-17,8- ol, formate (10.0 g.) and absolute ethanol (1.0 l.) and reflux the reaction mixture with stirring for 5 hours. Filter the reaction mixture while hot through filter aid. Wash the filter cake with ethanol then with methylene chloride and evaporate the combined filtrate in vacuo. Dissolve the residue in ether, wash, dry and evaporate the extract, then treat the resulting oil in methylene chloride with decolorizing charcoal, filter and evaporate the solvent in vacuo. Crystallize the residue from absolute ethanol to get 4.85 g. of title product, M.P. l72-176 C. Repeat the above purification by charcoaling to obtain from isopropanol, 3.86 g. of title product, M.P. 179-181 C. Further purify a sample (1.20 g.) by chromatography in benzene on Florex XXS (Floridin Company brand of fluorosilicate), remove the solvent in vacuo and crystallize the residue from absolute ethanol to obtain 1.00 g. of theC pure title product as white needles, M.P. 183 185 Analysis. -Calcd. for C H O (percent): C, 74.56; H, 8.16. Found (percent): C, 74.33; H, 7.90.

EXAMPLE 5 17 fl-acetyl-l 3-ethyl-3-methoxygona- 1,3,5 (10)- triene (alternative procedure) Add a solution of dl-l7a-acetyl-13-ethyl-3-methoxygona-1,3,5(10)-trien-17B-ol, formate (1.50 g.) in dioxane (50 ml.) to a solution of calcium metal (1.0 g.) in liquid ammonia (400 ml.), stir for 1 hour then quench the reaction mixture With ammonium chloride (5 g.). Add water, filter and dry the resulting white precipitate. Treat the solid in methylene chloride with decolorizing chart 5.92;]. When the acetate is substituted for the formate in the above reaction, substantially the same results are obtained.

EXAMPLE 6 v l7fl-acetyl-13-ethylgon-4-en-3-one (alternative procedure) Add a solution of dl-17a-acetyl-13-ethyl-3-methoxygona-1,3,5(10)-trien-17fi-ol, formate (.40 g.) in dioxane (100 ml.) to a solution of lithium metal (2.0 g.) in liquid ammonia (1.0 liter), stir for 1 hour then add t-butyl alcohol (250 ml.) dropwise to the stirred reaction mixture, stir for 1 hour after addition then add a further 8.0 g. of lithium metal and stir 1 hour. Add methanol dropwise until the blue color is discharged. Add water, filter and dry the resulting white precipitate. Treat the solid in methylene chloride with anhydrous sodium sulfate, filter and remove the solvent in vacuo. Cover the resulting solid with methanol (150 ml.) and 4 N hydrochloric acid (50 m1.) and boil the mixture on the steam bath for 30 minutes. Cool, stir at room temperature for 1.5 hours then add water (400 ml.) and extract the mixture with ether. Wash, dry and evaporate the extract in vacuo and dissolve the residue in acetone (150 ml.). Cool the solution in an ice-bath, add anhydrous sodium sulfate (5 g.), then with stirring add 8 N chromic acid solution 10 ml.) dropwise, stir for minutes more, then add isopropanol ml.) and water (500 ml.) and filter the resulting white crystalline precipitate. Treat the solid in methylene chloride with decolorizing charcoal and sodium sulfate, filter and evaporate the solvent in vacuo. Crystallize the oil from acetone-hexane to get 1.15 g. of the title product, M.P. 144-146 C.;

A 5.90 and 6.02 239 mp (e 16,900)

max.

EXAMPLE 7 17-acetyl-13-ethylgona-4,16-dien-3-one (a) dl-13-ethyl 17 ethynylgona 4,10 dien-3-one.-- Cool pyridine (400 ml.) in an ice-bath, then slowly add phosphorus oxychloride (60 ml.), stir and add dl-13- ethyl 17a. ethynyl-17B-hydroxygon-4-en-3-one g.). Heat the reaction mixture to mild reflux for 10 minutes, cool (ice-bath) then carefully pour the reaction into a mixture of ice and water and concentrated hydrochloric acid (500 ml.). Add some ether and stir the resulting mixture until most of the solids have broken up and passed into the ether phase. Extract the mixture with ether, then wash and dry the extract. Filter and evaporate the solvent in vacuo and crystallize the resulting oil from methanol to obtain 8.0 g. of the title compound, M.P. 129132 C. The pure sample from methanol has M.P. 132-135 C.;

A 35. 3.12, 4.85 and 6.04 A212? 236 my (6 23,600).

(b) dl-17-acetyl 13 ethylgona-4,16-dien-3-one.-Filter 200 ml. of mercurated Dowex 50W-2X resin (a cation exchange resin marketed by Dow Chemical Co., Midland, Mich., activated as described in Example 1(b) wash the filter cake with water and absolute ethanol. Mix the resin in a reaction flask with water (60 ml.), absolute eth'anol '(300 ml.) and a solution of dl-13-ethyl-17-ethynylgona-4,16-dien-3-one (8.00 g.) in absolute ethanol (500 ml.) and reflux the mixture with stirring for 5 hours. Filter the hot mixture through filter aid and Wash the filter cake with ethanol and methylene chloride. Evaporate the combined filtrates in vacuo, dissolve the residue 28 in methylene chloride, wash, dry and evaporate the sol: vent'in vacuo. Cry'stallize the residue from benzene-hex-' ane to get 5.00 g of title product, M.P. 171-174 C. Obtain second crops of 0.45 g., M.P. 172-175 C. Obtain an' analytical sample by treating 1.75 g. in methylene chloride with decolorizing charcoal, filtering and replacing the solvent with benzene-hexane to get 1.08 g. of pure title product, M.P. 175-177 C.;

) Et0H i 6.03 1; mm 241 111;].(624 600).

Aanalysis.Calcd. for C H O (percent): C, 80.73; H, 9.03. Found (percent): C, 80.84; H, 8.73.

EXAMPLE 8 17,8-acetyl-13ethylgon-4-en-3-one (alternative procedure) Pre-treat a mixture of 5% palladium on carbon (0.25 g.) and absolute ethanol (50 ml.) with hydrogen at 1 atmosphere. Add a solution of dl-17-acetyl-13-ethylgona- 4,16-dien-3-one (1.00 g.) and treat the solution with hydrogen until just slightly over one equivalent amount of the gas is absorbed (ca. ml.). Filter the reaction mixture through filter aid and evaporate the solvent in vacuo to obtain the title product.

EXAMPLE 9 17,8-acetyl-13-ethyl-5/3-16a-dimethylgon-3-one EXAMPLE 10 17B-acetyl-13-ethyl-16a-methylgon-4-en-3-one (a) dl 17B acetyl 13 ethyl-16a-methyl-3-methoxygona-1,3,5(10)-triene.Dilute a 3 M ethereal solution of methyl magnesium iodide (10 ml.) under nitrogen with ether (50 ml.), stir and add cuprous chloride (400 mg).

Add a suspension of dl-l7-acetyl-13-ethyl-3-methoxygonae.

1,3,5(10),16-tetraene (1.50 g.) and ether ml.) then reflux the mixture gently for 2 hours. Cool, quench the reaction by the dropwise addition of saturated ammonium chloride solution, filter then wash, dry and evaporatethe ethereal layer. Treat the resulting oil in methylene chloride with decolorizing charcoal, filter and evaporate the solvent in vacuo. Crystallize the oil from absolute ethanol to obtain 0.90 g. of title product, M.P. 130-132 C. Further purify a sample (0.80 g.) by passing a benzene solution through a column of anhydrous, neutral alumina, evaporating the solvent in vacuo and crystallizing the residue from absolute ethanol to obtain 0.59 g. of the pure title product, M.P. 137139 0.;

his; 5.93;!"

Analysis.-Calcd. for C H O (percent): C, 81.13; H, 9.47. Found (percent): C, 81.29; H, 9.74.

one.Add a solution of dl-17/3-acetyl-13-ethyl-16mmethyl-3-methoxygona-1,3,5(10)-triene (4.5 g.) in diox-' ane (100 ml.) to a solution of lithium metal (2.0 g.) in

liquid ammonia (1 liter) and stir for 1 hr. Add t-butyl alcohol (200 ml.) dropwise over 1 hour, then add more lithium metal (8.0 g.) and stir a further 2 hours. Add methanol dropwise until the blue color is discharged, add water then filter and dry the resulting white precipitate. Add the solid to a mixture of methanol (180 ml.), water (12 ml.) and concentrated hydrochloric acid (10 ml.).

Reflux the mixture for 10 minutes then stir at room temperature for 2 hours. Add water (700 ml.), extract with ether then wash, dry and evaporate the ether in vacuo. Dissolve the resulting oil in acetone (200 ml.) and anhydrous sodium sulfate (5 g.) and cool the mixture with an ice-bath. Add 8 N chromic acid solution (10 ml.) dropwise to the stirred mixture, stir minutes more than add isopropanol m1.) and water (500 ml.) and extract the mixture with ether. Wash, dry andevaporate the extract in vacuo. Pass the resulting oil in benzene through a column of anhydrous neutral alumina, evaporate the solvent in vacuo and recrystallize the residue from absolute ethanol to get 2.70 g. of the pure title product, M.P. 179-181" C.;

2152.15.93 and 6.03,.; 239 111,. (6 16,000).

EXAMPLE 11 ECOH mat.

17-acety1-13-ethyl-3-methoxy-16-methylgona- 1,3,5 (10)-16-tetraene (a) dl 17,3-acetyl-13-ethyl-3-methoxy-16a,17a-methyleneazogona-1,3,5 (10)triene.Treat dl-17-acetyl-13-ethyl- 3-methoxygona-1,3,5(10),16-tetraene (3.00 g.) with an ethereal solution of diazomethane by covering 50% aqueous potassium hydroxide solution (20.0 g. in water) with the substrate in ether (350 ml.), then cooling with an ice-bath and adding N-nitroso methylurea (7.0 g.) in small portions. Stand at room temperature for 3 hours, then add another portion (7.0 g.) of N-nitroso methylurea portionwise at ice-bath temperature and dilute the reaction with another 150 ml. of ether. Allow the solution to stand overnight at room temperature then add the solution to a shallow dish containing water (300 ml.) and gently boil off the ether. Filter the resulting oil-white solid to obtain 3.35 g. of title product, M.P. 142-144 C. (decomp.). Treat the sample in methylene chloride with decolorizing charcoal, filter and evaporate the solvent in vacuo. Crystallize the residue from ethanol and let stand to obtain 2.39 g. of title product, M.P. ISL-153 C.;

Repeat the above purification on 0.35 g. of sample to obtain from ethanol 0.26 g. of pure title product, M.P. 157-159 C. (decomp.).

(b) dl 17-acetyl-13-ethyl-3-methoxy-16-methylgona-1, 3,5 10) ,16-tetraene.Acld dl-l7fl-acetyl-13-ethyl-3-methoxy-16u,17a-methyleneazogona-1,3,5(10)-triene (2.00 g.) portionwise to well stirred diethylene glycol ml.) heated to 185 C. (bath) over a period of 25 minutes and continue heating and stirring for a further 10 minutes. Cool, add water and filter the solid onto filter aid. Extract the filter cake with methylene chloride dry, filter and evaporate the solvent in vacuo. Crystallize the residue from ethanol to obtain the title product, M.P. 149- 150 C.;

x51; 252p, (e 7,300).

EXAMPLE 12 d-17p-acetyl-10,13-dimethylgon-4-en- 3-one (progesterone) 30 EXAMPLE 13 d-17a-acetyl-3-methoxyestra-1,3,5(10)- trien-17p-0l, acetate (a) d-l7m-ethynyl-3-methoxyestra-l ,3,5 (10)-trien-17flol acetate.-To a solution of acetic anhydride ml.) and 70% perchloric acid (1.4 ml.) in ethyl acetate (1400 ml.) add d-17a-ethynyl-3-methoxyestra-1,3,5(10)-trien- -01 (14.0 g.). Swirl the solution and let stand at about 23 C. for 2.5 minutes, then quench the clear solution with saturated sodium bicarbonate solution. Wash the organic layer with sodium bicarbonate solution and with brine, dry over anhydrous sodium sulfate, filter, and remove the solvent in vacuo. Cover the residue with methanol (400 ml.) and pyridine (1 ml.), boil for 10 minutes, cool and evaporate in vacuo. Remove the traces of pyridine and acetic acid by dissolving the residue in toluene, evaporating in vacuo and pumping the residue in vacuo. Dissolve the resulting solid in methylene chloride, treat with decolorizing charcoal, filter and replace the solvent wth absolute ethanol by boiling. Let stand to deposit 15.0 g. of the title product as large white prisms, M.P. 158-160" C.;

r55; 3.12 and 5.76,..

[ab +4 (c., 1% in chf.).

(b) d-17m-acety1-3-methoxyestra-1,3,5, 10)-trien-17- 3- ol, acetate.--Reflux amixture of d-17a-ethynyl-3-methoxyestra-1,3,5(10)-trien-17;8-ol, acetate (4.00 g.) and powdered silver nitrate (400 mg.) in dioxane (200 ml.) and water (40 ml.) for 2% hours. Cool and add water (300 ml.) then extract the mixture with ether. Wash the extract with water and brine, dry and evaporate the solvent in vacuo. Triturate the residue with methanol and filter to get 3.00 g. of crude title Product, M.P. 146-149 C. Dissolve a sample (2.59 g.) of the solid in benzene and pass the solution through a column of anhydrous neutral alumina. Remove the benzene in vacuo and treat the residue in methylene chloride with decolorizing charcoal, filter and evaporate in vacuo. Replace the solvent with absolute ethanol by boiling, let stand then filter to get 0.67 g. of pure title product, M.P. 162-164 C.;

REEL 5.80 and 5.87

Analysis.Calcd. for C H O (percent): C, 74.56; H, 8.16. Found (percent): C, 74.49; H, 7.77.

EXAMPLE 14 l7a-acetyl-13-ethyl-3-methoxygona- 1,3,5,(10)-trien-17p-ol, acetate (a) dl-l3-ethyl-17a-ethynyl-3-methoxygona-1,3,5 10)- trien-17/3-ol, acetate-To a solution of acetic anhydride (28.8 ml.) and 70% perchloric acid (0.30 ml.) in ethyl acetate (300 ml.) add dl-13-ethyl-17m-ethynyl-3-methoxygona-1,3,5(10)-trien-l7}3-0l (3.00 g.). Swirl the reaction and let stand at about 23 C. for 3.5 minutes then quickly quench the clear solution by adding saturated sodium bicarbonate solution. Wash the organic layer several times with'saturated sodium bicarbonate solution, with brine, then dry the extract over anhydrous sodium sulfate. 'Filter and remove the solvent in vacuo then add methanol (300 ml.) and pyridine (1 ml.) and boil on the steam bath for 10 minutes. Cool and remove the solvent in vacuo. Add toluene and remove it in vacuo several times to remove traces of pyridine and acetic acid, then pump dry. Triturate the residue with methanol and filter to get 3.22 g. of the title product, M.P. 171-173 C. Further purify a sample (1.00 g.) by treating a solution in methylene chloride with decolorizing charcoal, filtering then replacing the solvent with absolute ethanol by boiling on the steam bath. Let stand to crystallize then filter to obtain 0.85 g. of the pure title product, M.P. 175177 C.;

my; 3.13 and 5.30,.

Analysis.-Calcd. for C H O (percent): C, 78.65; H, 8.25. Found (percent): C, 78.63; H, 8.21.

(b) (ll-17a acetyl-13-ethyl-3-methoxygona-l,3,5(10)- trien-l7fl-ol, acetate.Reflux a mixture of dl-13-ethyl- 17a ethynyl-3-methoxygona-1,3,5(10)-trien-17fl-ol, acetate (1.0 g.) and powdered silver nitrate (0.10 g.) in dioxane (50 ml.) and water (10 ml.) for 3 hours. Cool, add water (200 ml.) then extract the mixture with ether. Wash the extract with water and brine, dry over anhydrous sodium sulfate, filter and evaporate the solvent in vacuo. Triturate the residue with cold methanol. Filter the resulting solid to get 0.51 g. of title product, M.P. l41-144 C.;

REE; 5.78 and 5.88

EXAMPLE 15 dl-17B-acetyl-13-ethyl-l6fi-mehyl- 3-methoxygona-1,3,5( 10) -triene (a) dl-13-ethyl-3-rnethoxy 16 methylenegona-1,3,5 (10)-trien-l7-one.-Refiux a mixture of dl-13-ethyl-3- methoxygona-1,3,5(10)-trien-17-one (40.0 g.), paratormaldehyde (15.0 g.), demethylamine hydrochloride (60.0 g.) and dry dioxane (500 ml.) into a Sohxlet extractor charged with 75 inch number 4A molecular sieves for 2 hours. Add another 15.0 g. of paraformaldehyde and continue refluxing for 3 hours. Cool and remove the solvent in vacuo. Digest the residue with a solution of potassium carbonate (120 g.) in water (600 ml.) then extract well with ether-methylene chloride (using enough ether to keep the organic layer less dense than the aqueous layer). Wash, dry and evaporate the extract in vacuo, then crystallize the residue from methanol to obtain 37.0 g. of title product, M.P. 142-145 C. Obtain an analytical sample from absolute ethanol, M.P. 146l48 C.;

x55; 5.31 and 6.09 A223? 225 my. (e 15,200).

Analysis.Calcd. for C H O (percent): C, 81.25; H, 8.44. Found (percent): C, 81.06; H, 8.36.

(b) dl 13 ethyl 3 methoxy-16p-methylgona-l,3,5- (10)-trien-17-one.-Pre-treat a mixture of 5% palladium on carbon 1.0 g.) and absolute ethanol (50 ml.) with hydrogen at one atmosphere then add a solution of d!- 13-ethyl-3-methoxy-l6-methylenegona 1,3,5 ()-trien- 17 one (3.00 g.) in ethanol-tetrahydrofuran (200 ml.) and continue to treat with hydrogen until uptake of one equivalent of gas is complete. Filter and evaporate the solvent in vacuo. Treat the residue in methylene chloride with decolorizing charcoal, filter and replace the solvent with ethanol by boiling. Let stand to complete crystallization then filter to obtain 2.67 g. of the pure title product, M.P. l46-150 C.;

(c) dl-13-ethyl-17a-ethynyl 3 methoxy-16fi-methylgona-1,3,5(10)-trien 17B ol.Dissolve dl-13-ethy1-3- methoxy-16B-methylgona-1,3,5(10)-trien 17 one (10.0 g.) in benzene (100 ml.) and dry dimethylsulfoxide (250 ml.) then bubble purified acetylene gas through the solution for one hour. Add lithium acetylide-ethylene diamine diamine complex (5.0 g.) and stir the solution under acetylene for one hour. Add 5.0 g. more of the reagent complex and stir a further one hour under acetylene. Pour the reaction into ice-water, extract with ether then wash, dry and evaporate the ether in vacuo. Add ether and let stand at 10 C. then filter the dimeric by-product. Evaporate the filtrate in vacuo and pump the resulting -oil under high vacuum. Dissolve the oil in a small amount of ether and scratch to induce crystallization. Let stand until crystallization is complete then add heptane and triturate the solid. Filter to obtain 5.6 g. of the title product, M.P. 108-111 C. Obtain an analytical sample from heptane, M.P. 124-l27 C.;

REE. 2.92 and 3.08;.

Y 17a-ethynyl 3 methoxy-16p-methylgona 1,3,5 10)- trien-17 8-o1 (4.50 g.) Stir and heat the reaction to re flux and continue boiling for- 25 minutes. Coolto below room temperature and carefully .pour thereaction into ice water. Extract the mixture with ether then wash, dry and evaporate the ether in vacuo. Pump the residue dry then dissolve in hexane containing a small, amount of ether and pass the solution through ,ashort column of lfluorosilicate. Remove the solvent in vacuo. Scratch the resulting oil in isopropanol then filter to obtain 0.80 of the title compound, M.P. 126-129 C. Obtain an analytical sample from isopropanol, M.P. 129-1319.

Riff. 3.1 and 4.83M A22? 228 mu (6 16,600)" Analysis.-Calcd. for C H O (percent): C, 86.20; H, 8.81. Found (percent): C, 85.85; H, 8.90.

(e) a l-17 acetyl 13 ethyl- 3-methoxy-l6-methylgona-1,3,5(10)-16-tetraene.Filter 15 ml. of the specially prepared mercurated Dowex 50W-X8 cationic resin (prepared as described in Example I), wash the resin with water then with absolute ethanol. Reflux a mixture of the above resin, water (5 ml absolute ethanol ml.) and dl-l3-ethyl 17 ethynyl-3-methoxy-16-methyl gona-1,3,5(10),l6-tetraene',(0.50 g.) for 5.5 hours. Filter the hot reaction through filter aid and evaporate thefi ltrate in vacuo. Dissolve the residue in methylene chloride, treat with decolorizing charcoal, filter and remove the solvent in vacuo. Dissolve the resulting oil in hot ethanol and let stand to complete crystallization. Filter to obtain 0.41 g. of the title product, M.P. 148 150 C.;

X 6.10m k 252 mg (6 7,300)

(f) dl-17fi-acetyl 13 -'ethyl-l6fl-methyl-3-methoxy gona-1,3,5(10)-triene.Pretreat a mixture of 10% palladized charcoal (1.3 g. and'absolute ethanol (100 ml.) with hydrogen at one atmosphere. Then add a solution of dl 17 acetyl-13-ethyl-16-methy1-3' methoxygona- 1,3,5(10),16-tetraene (4.00 g.) in tetrahydrofuran (300 ml.) and absolute ethanol (300 ml.) and continue hydrogenating until uptake of the gas is complete (10-15 minutes). Filter and evaporate the.solvents in vacuo. Dissolve the resulting oil in methylenechloride, treat with decolorizing charcoal, filter and remove the solvent in vacuo. Dissolve the resulting 3.24 g. of the title product as a granular white solid, M.P. 110-111 C. Obtain an analytical sample from ethyl acetate-hexane having M.P. 109-111" C.; r I

Analysis.Calcd. for C H O (per cent): C, 81.13; H, 9.47. Found (percent): C, 80.83; H,"9.11. 1

EXAMPLE 16- 1 dl-17p-acety1- 13-ethyl-l 6p-methylgon-4en-3-one,

Add a solution of dl-17B-acetyl-13-ethyl-l6fi-methyl-3- methoxygona-1,3,5(10)triene (3.76 g.) in dry dioxane (100 ml.) to a solution of lithium metal (2.0 g.) in purified liquid ammonia (700 ml.) and stir for 1 hour. Add t-butanol (200 ml.) dropwise over /2 hour, stir a further 16 hour then again "add lithium metal (8.0 g.). Stir for 2 hours then add methanol dropwise until the blue color is discharged. Add hot water, filter-and dry the resulting white precipitated 2,5(10)-diene. Cover the ,solid,.- .withmethanol ml.), water 12 ml.) and concentrated hydrochloric acid (35 ml.).- Boil the mixture for 10minutes, cool and stir at room temperature for 1 hour. Ex-

tract the mixture with ether. Wash the extract with water,-

saturated sodium bicarbonate solution, water, brine' and then dry over anhydrous sodium sulfate. Filter; and evaporate the solvent in vacuo. Dissolve the resulting oil. (gon-4-en-3-one-20E-ol) in anhydrous acetone (200 ml.),

cool with an ice-bath then add anhydrous sodium sulfate g.). To the cooled solution and 8 N chromic acid solution (8 n11.) dropwise and with stirring over /2 hour. Add isopropanol ml.) and water (500 ml.) then extract the mixture with ether. Wash and dry the extract, evaporate the solvent in vacuo to an oil. Crystallize the oil from methanol to get 0.95 g. of the title product, M.P. 132- 134 C. Dissolve the solid in methylene chloride, treat with decolorizing charcoal, filter and remove the solvent in vacuo. Crystallize the residue from methanol to obtain 0.30 g. of pure title product, M.P. 135137 0.;

x55; 5.91 and 6.02; A532? 4 Analysis.-Calcd. for C d-E 0 (percent): C, 80.44; H, 9.83. Found (percent): C, 80.28; H, 9.71.

Obtain combined second crops from the above crystallization of 0.79 g., M.P. 130-132 C.

methyl-3-methoxygona-3,S-diene. Dissolve the material in tetrahydrofuran (20 ml.) and methanol (50 ml.), cool with an ice-bath then add 50% sodium hydroxide solution (7 ml.). Stir the cooled reaction for /2 hour and add water (300 ml.) and extract the mixture with ethyl acetate. Wash and dry the extract and evaporate the sol- Vent in vacuo to get dl-13-ethyl-6-fonnyl-17fi-( l-hydroxyethyl)-16a-methyl-3-methoxygona-3,5-diene. Dissolve the material in methanol (100 ml.), cool with an ice-bath then with stirring add sodium borohydride (5.0 g.). Stir for /2 hour then quench with water (250 ml.) and extract the mixture With ether-ethyl acetate. Wash, dry and evaporate the extract in vacuo to obtain dl-13-ethy1-6-hydroxymethyl 17fi-(1hydroxyethyl)-16m-methyl-3-methoxygona-3,5-diene. Dissolve this product in methanol (75 ml.), cool with an ice bath then with stirring add 8 N sulfuric acid solution (10 drops). Stir for /2 hour, then add a further 25 ml. of methanol and 10 drops of 8 N sulfuric acid solution. Stir the cooled reaction a further A2 hour then dilute with Water and extract the mixture with ether-ethyl acetate. Wash, dry and evaporate the extract in vacuo to obtain dl-13-ethyl-6-methylene-l7fi- (l-hydroxy-ethyl)-16a-methylgon-4-en 3 one. Dissolve the product in cyclohexene. ml.) and absolute ethanol (300 ml.) then add 5% palladized charcoal (1.0 g.) and benzyl alcohol /2 ml.). Reflux the mixture for 4 hours, cool and filter then add concentrated hydrochloric acid /2 ml.) to the filtrate. Evaporate the filtrate in vacuo, add Water and extract the mixture with ether. Wash, dry and evaporate the extract in vacuo to get dl-l3-ethyl-l7 8- (l-hydroxyeth'yD-6u,l6a-dimethylgon-4-en 3 one. Dissolve this product in anhydrous acetone 100 ml.), add anhydrous sodium sulfate (5 g.) then cool with an icebath. With stirring and 8 N chromic acid solution (10 ml.) dropwise over /2 hour. Stir a further 10 minutes then quench the reaction with isopropanol (25 ml.) and water (500 ml). Extract the mixture with ether, Wash, dry then evaporate the extract in vacuo. Dissolve the resulting oil in benzene and pass the solution through a short column of anhydrous neutral alumina. Evaporate the benzene in vacuo and crystallize the residue from cold methanol to obtain the title product.

EXAMPLE 18 d l- 17 ,B-acetyl-6 0c, 16/8-dimethyl-l3-ethylgon-4-en-3 -one The procedure of Example 17 is repeated, substituting for the dl-13-ethyl-17;S-(l-hydroxyethyl)-1'6u-methyl-3- methoxygona-2,5(10-diene and there is obtained, first, dl- 13 -ethyl 6 formyl 17B (1 formyloxyethyl)-16B methyl-3-methoxygona-3,5-diene; second, dl-13-ethyl-6- formyl 17/3 (1 hydroxyethyl) l6fi-methyl-3-meth oxygoria 3,5 diene; third, dl-l3-ethyl-6-hydroxymethyl- 17/3 (1 hydroxyethyl) 165 methyI-B-methoxygona- 3,5 diene; fourth, dl 13-ethyl-6-methylene-17B-(l-hydroxyethyl) 16 3 methylgon 4 en-3-one; fifth, dl-l3- ethyl 17B (1 hydroxyethyl)-6a,16,B-dimethylgon-4- en-3-one, and, finally, the title product.

dl 17,6 acetyl -6,16B dimethyl 13-ethylgona-4,6- dien-3-one is prepared by refluxing dl-13-ethyl-6-methylene 17B (1 hydroxyethyl) 16,8 methylgon-4-en-3- one mg.), sodium acetate (50 mg.) and Pd/C (5%, 15 mg.) in absolute ethanol (30 ml.) for 1.5 hrs. The mixture is cooled to about 23 C., diluted with ether, filtered through filter aid, washed with aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate and stripped in vacuo. The solid residue is recrystallized from ether to give the 4,6-diene product.

EXAMPLE 19 dl-17-acetyl-13-ethylgona-5,16-dien-3/3-ol, acetate (a) all 13 Ethyl 17a ethynylgon-5-one-3fi,17fldiol, 3-acetate.Prepare a solution of acetic anhydride (190 ml.) and 70% perchloric acid (7 ml.) in ethyl acetate (2 1.) then add dl-l3-ethyl-17a-ethynyl-l7;8-hydroxygon-4-en-3-one (40.0 g.) and swirl to fully dissolve. Let the reaction stand at about 23 C. for 3 minutes then quench the clear solution with saturated sodium bicarbonate solution. Wash the organic layer with saturated sodium bicarbonate solution and brine, dry and evaporate the solvent in vacuo. Dissolve the residue in methanol (300 ml.) and pyridine (1 ml.), boil for 10 minutes, cool and evaporate the solvent in vacuo. Dissolve the residue in toluene and evaporate in vacuo several times to remove acetic acid and pyridine then recrystallize the residue from methanol. Filter to obtain 37.0 g. of dl-13-ethyl- 17u-ethynylgona-3,5diene-3,l7,8-diol, diacetate, M.P. 160- 164 C. Dissolve this compound in tetrahydrofuran (300 ml.) and methanol (500 ml.) and cool with an ice bath. With stirring add sodium borohydride (50 g.) in small portions over two hours (keep cool). Stir a further 18 hours at room temperature then add water (1 l.) and extract with ether. Wash, dry and evaporate the extract in vacuo to get dl-l3-ethyl-l7u-ethynylgon-5-en-3B,17fi-diol, 17-acetate. Obtain a pure sample from ethanol, M.P. 146-148 0.;

LEE; 3.05, 3.09 and 5.76;;

Cover the above product with methanol (600 ml.), cool with an ice bath then add sodium methoxide (20.0 g.) and stir the cooled reaction for 1 hr. and at about 23 C. a further 2 hr. Add water (1 liter) dropwise, extract the mixture with ether-ethyl acetate then wash, dry and evaporate in vacuo to obtain dl-13-ethyl-17aethynylgon 5 en 313,17fl-diol. Obtain a sample from methanol (as a methanol solvate), M.P. l1912l C. (evolution of solvent). Dissolve all of this produce in pyridine (500 ml.) add acetic anhydride ml.) and allow the reaction to stand at about 23 C. for 16 hrs. Pour the reaction into water and let stand for 1 hour. Extract with ethyl acetate then wash, dry and evaporate the extract in vacuo to an oil. Dissolve the oil in methylene chloride, treat with decolorizing charcoal, filter and evaporate the solvent in vacuo. Dissolve the resulting oil in methanol and let stand to obtain 26.0 g. of the title product (dl-13- ethyl 17oz ethynylgon-5-ene-3/3,17,8-diol, 3-acetate), M.P. 172-174 0.;

x53, 296,814. and 5.82,

Analysis.-Calcd. for C H O (percent): C, 77.49; H, 9.05. Found (percent): C, 77.32; H, 8.66.

(b) dl-13-ethyl 17 ethynylgona-S,16-dien-3p-ol, acetate.Cool pyridine (60 ml.) in an ice-bath, add phosphorus oxychlon'de (9 ml.) dropwise and with stirring then add dl-I3-ethyl-17a-ethynylgon-5-ene-3B,17/3-diol, 3- acetate (3.00 g.) and gently reflux the reaction for 10 minutes. Cool, carefully pour into ice-water and extract the mixture with ether. Wash, dry and evaporate the extract in vacuo and crystallize the residue from methanol to obtain 0.60 g. of the title product, M.P 119122 C.;

A525, 3.14 and 5.82p.

(c) dl-13-acetyl-13-ethylgona 5,16 dien-Sfl-ol, acetate-Reflux a mixture of mercurated Dowex 50W-X8 cationic resin (15 ml.) ethanol (100 ml.) and dl-13- ethyl-17-ethynylgona-5,16-dien-3p, acetate (0.57 g.), for 4 hours. Filter the hot reaction mixture through filter aid, wash the filter-cake with methylene chloride then evaporate the combined filtrates in vacuo. Scratch the resulting oil with a small amount of ether, triturate the solid with methanol and filter to obtain 100 mg. of the title product, M.P. 127129 C.;

AL, 5.80 and 6.05 4.

EXAMPLE 20 di-173-Acetyl-13-ethyl-16a-methyl-3-methoxygona- 1,3,5 10) -trien-17a-o1 (a) dl-13-ethyl-17-(l-acetoxyethylidene) 16a methyl 3 methoxygona-1,3,5(10)-triene.To dry tetrahydrofuran (250 ml.) and 3 M ethereal methyl magnesium bromide (90 ml.), stir then cool the clear solution with an ice-methanol bath and under nitrogen add cuprous chloride (2.0 g.). Stir cold for 10 minutes then add a solution of dl 17 acetyl-13-ethyl-3-methoxygona 1,3, (),16-tetraene (25.0 g.) in warm dry tetrahydrofuran (250 ml.), dropwise over minutes to the cooled reaction. Rinse the addition funnel with a further 100 ml. of dry tetrahydrofuran, add this to the reaction then stir cold for 10 minutes and at room temperature for one hour. Cool the reaction again with an ice-methanol bath and with stirring, under nitrogen add a solution of freshly distilled acetyl chloride (25 ml.) in dry tetrahydrofuran (100 ml.) dropwise. Stir cold a further 5 minutes then at room temperature for 20 minutes. Cool the reaction again with an ice-methanol bath and add 10% aqueous ammonium chloride solution (600 ml.) dropwise with stirring. Extract the reaction with ether then wash, dry and evaporate the extract in vacuo. Dissolve the resulting oil in methanol, filter then evaporate the methanol to low volume in vacuo. Let stand to deposit 22.5 g. of the title product, M.P. 108-ll1 C.

(b) dl-17fl-acetyl-13-ethyl 16oz methyl-3-methoxygona-1,3,5(10)-trien-17-ol.To a solution of dl-13-ethyl-17 (l-acetoxyethylidene) 16oz methyl-3-methoxygona-1,3,5(10)-triene (25.0 g.) in ether (600 ml.) and mchloroperbenzoic acid (30.0 g.) and stir at room temperature for 24 hours. Wash the extract well with 5% aqueous potassium carbonate, with water and brine then dry and evaporate the solvent in vacuo. Dissolve the resulting oil in methanol (350 ml.) and add a solution of potassium carbonate 10.0 g.) in water (50 ml.) then gently boil the mixture for 45 minutes. Cool and dilute the reaction with water then extract with ethyl acetate-ether. Wash, dry and evaporate the extract in vacuo. Triturate the residue with hexane and filter to get 14.0 g. of the crude title product. Obtain a pure sample of the title product by chromatography on fluorosilicate and crystallization from ether then from methanol; M.P. 160- 162 C.;

2.92 and 5.93

Analysis.-Calcd. for C H O (percent): C, 77.49; H, 9.05. Found (percent); C, 7. .3 H, 8.70.

36 EXAMPLE 21 d!-17fl-acetyl-13-ethyl-l613-methyl-3-methoxygona- 1,3,5 10) -trien-17a-ol (a) dl-l3-ethyl 17 (l-acetoxyethylidene)-16B-methyl-3-methoxygona 1,3,5(10)-triene.To a solution of acetic anhydride (9.6 ml.) and 70% perchloric acid (0.1 ml.) in ethyl acetate (200 ml.) add dl-17/3-acetyl-13-ethyl- IGB-methyl 3 methoxygona-1,3,5(10)-triene (2.00 g.), swirl the mixture and let the reaction stand at about 23 C. for 5 minutes. Quench the clear solution with saturated sodium bicarbonate solution. Wash, dry and evaporate the organic layer than add methanol (200 ml.) and pyridine (1 ml.) and boil for 10 minutes. Cool and evaporate the solvent in vacuo then triturate the residue with cold methanol to obtain the title product.

(b) dl-17B-acetyl 13 ethyl-l6fi-methyl-3-methoxygona-1,3,5(10)-trien-l7a-ol.The product of step (a), this example, is converted by the procedure of step (b), Example 20, to the named product.

EXAMPLE 22 dl-17fl-acetyl-13-ethyl-16fl-methyl-3-methoxygona- 1,3,5 10)-trien-17u-ol, alternative procedure Treat a solution of dl-17B-acetyl-13-ethyl-16/3-methyl- 3-methoxygona-1,3,5(10)-triene (5.0 g.) and potassium t-butoxide (5.0 g.) in t-butanol (500 ml.) with oxygen at one atmosphere, with shaking until uptake of the gas is complete. Add a solution of glacial acetic acid (50 ml.) in water ml.) and remove the t-butanol by evaporation in vacuo. Add water (300 ml.) and let stand at 0 C. Filter and dry the resulting solid in vacuo. Dissolve the solid in ethanol (70 ml.) and add acid-washed zinc dust (10.0 g.). Stir the reaction for 5 hours at room temperature then filter and wash the filter-cake with ethyl acetate. Dilute the filtrate with water (500 ml.) and extract with ethyl acetate. Wash, dry and evaporate the extract to obtain the title compound.

EXAMPLE 23 dl-17p-acetyl-13-ethyl-17a-hydroxy-16a-methylgon- 4-en-3-one (a) dl-13-ethy1-17B-(l-hydroxyethyl) 16oz methyl-3- methoxygona-1,3,5(10)-trien-17a-o1.Stir a mixture of di-17p-acetyl-13-ethyl-16u-methyl 3 methoxygona-1,3, 5(10)-trien-17a-ol (29.5 g.) and methanol (600 ml.) then add sodium borohydride (30.0 g.) in small portions with stirring over 4 hours. Allow the reaction to stand for 17 hours then add water (1500 ml.) dropwise and with stirring to fully precipitate the product. Filter and dry to obtain 26.0 g. of crude title product, M.P. 98-105" C. k 2.92,u. Obtain a pure derivative of the title product by dissolving a sample in acetone, adding several drops of 70% perchloric acid and stirring at room temperature for 3 hours. Quench with saturated sodium bicarbonate solution and extract with ether. Wash dry and evaporate the extract in vacuo then dissolve the resulting oil in benzene. Pass the solution through anhydrous, neutral alumina then evaporate the solvent in vacuo to obtain a white solid. Recrystallize the solid from methanol to obtain pure dl-13-ethyl-17a,20 (isopropylidenedioxy) 3 methoxy-l6a-methyl-18,19-dinorpregna 1,3,5 10) triene, M.P. 156-158 C.

Analysis.--Calcd. for C H O (percent): C, 78.35; H, 9.61. Found (percent): C, 78.55; H, 9.86.

(b) dl-13-ethyl-17B-(1 hydroxyethyl) 16a methyl- 3-methoxygona-2,5(10)-dien 17a ol.To a solution of dl-13-ethyl17a-(l hydroxyethyl) 16a methyl-3-methoxygona-1,3,5 (10)-trien-17a-ol (26.0 g.) in dry tetrahydrofuran (600 ml.) add 1-methoxy-2-propanol (400 ml.), stir then add freshly distilled liquid ammonia (2500 ml.). To the stirring reaction add lithium metal (30.0 g.) in small portions at a rate to prevent vigorous refluxing of the ammonia, but fast enough to maintain a blue color. Stir a further 45 minutes after complete addition then add absolute ethanol dropwise to the stirred reaction until the blue color is discharged. Add ammonium chloride (210 g.) in small portions followed by hot water (1500 ml.) in small portions to drive off ammonia and bring the reaction to room temperature. Extract the mixture with ether then wash with water to neutrality. Dry and evaporate the solvent in vacuo. Triturate the residue with hexane and filter to obtain 18.0 g. of the title product, M.P. 164-169 C.

(c) dl-13-ethyl-17B-(1 hydroxyethyl) 17a hydroxy- 16a methylgon-4-en-3-one.-Add concentrated hydrochloric acid (6 ml.) and water (6 ml.) to methanol (75 ml.) containing dl-13-ethyl-17fl-(l-hydroxyethyl) 16amethyl-3-methoxygona-2,5(10)dien 17a 01 (2.00 g.). Stir the reaction at room temperature for one hour then dilute with water and extract the mixture with ether. Wash, dry and evaporate the extract in vacuo. Triturate the residue with ether-hexane and filter to get 1.54 g. of the title product, M.P. 167170 C.;

A 2.90 and 6.00 1; E12? 240 m (e 14,500)

(d) dl-17,B-acetyl 13 ethyl-17a-hydroxy-16m-methylgon-4-en-3-one.Dissolve dl-13-ethyl-17B-(1 hydroxyethyl) 17a hydroxy-16a-methylgon-4-3-one (2.93 g.) in dimethylsulfoxide (70 ml.) and dilute with acetic anhydride (15 ml.). Let the reaction stand for 20 hours at room temperature. Pour the reaction into water and extract the mixture With ether-ethyl acetate. Wash, dry and evaporate the extract in vacuo, then pump dry. Dissolve the oil in ether and let stand to crystallize. Filter to obtain 1.00 g. of the title product, M.P. 173-176 C. btain an analytical sample by treatment with decolorizing charcoal in methylene chloride solution and recrystallization from methanol to get the pure title product, M.P. 182-184 C.;

A5 3,, 2.93, 5.88 and 6.03 1; REL? 239 mu (6 17,100)

Analysis.-Calcd. for C l-1 0 (percent): C, 76.70; H, 9.36. Found (percent): C, 76.98; H, 9.21.

EXAMPLE 24 dl-17fi-acetyl-13-ethyl-17u-hydroxy- 16 8-methylgon-4-en-3-0ne (a) dl-13-ethyl-17 8-(1 hydroxyethyl) 16,8-methyl-3- methoxygona-l,2,4(10)-trien-17u-ol.For the substrate in Example 23, step (a), there is substituted dl-17B-acetyl- 13-ethyl-16 3-methyl 3 methoxygona 1,3,5 (10)-trien- 1711-01 and the title product is obtained.

(b) dl-17fl-acetyl-13-ethyl 17a. hydroxy 16p -methylgon4-en-3-one.-For the substrates in Example 23, steps (b)-(d) there are substituted the corresponding products of this example, steps (a)-(c) and the title prodnot is obtained.

EXAMPLE 25 dl-l7fl-acetyl-13-ethyl-17u-hydroxy-l6u-methyl-gon-4- en-3-one, acetate and 16p-methyl epimer thereof To a solution of acetic anhyride (4.8 ml.) and 70% perchloric acid (0.05 ml.) in ethyl acetate (75 ml.) add dl-17/8-acetyl-13-ethyl-17a hydroxy 16a methylgon-4- en-3-one (1.00 g.), swirl and let the reaction stand at about 23 C. for 5 minutes. Quench the clear solution by adding saturated sodium bicarbonate solution. Wash, dry and evaporate the organic extract in vacuo. Add methanol (150 ml.) and pyridine (1 ml.), boil for 5 minutes then cool and evaporate the solvent in vacuo. To the residue add methanol (150 ml.) and sodium carbonate (1.00 g.) then stir about 23 C. for 4 hours. Add water (200 ml.) and extract the mixture with ethyl acetate. Wash, dry and evaporate the extract in vacuo to obtain the title product.

For the above substrate substitute dl-17B-acetyl-13- ethy1-17a-hydroxy-l6B-methylgon-4-en-3-one to obtain all- 17B-acetyl-13-etliyl-l7a-hydroxy 16/8-methylgon-4-en-3- one, acetate.

3. EXAMPLE 26 dl-17-acetyl-13-ethyl-16-methylgona-5,16-dien- 3 fi-ol, acetate (a) dl 17/3 acetyl l3 ethyl 1611,1712: methyleneazogon 5 en-3fi-ol, acetate-Cover 50% sodium hydroxide solution ml.) with a solution of dl-l7-acety1- 13-ethylgona-5,1-6-dien-3'fl-ol, acetate (4.00 g.) in ether (500 ml.). Cool the mixture in an ice-bath, then add N- nitrosomethylurea (12.0 g.) in small portions over 2 hours with swirling. Let the reaction stand overnight at room temperature, then cool the reaction again in an ice-bath and again add N-nitrosomethylurea (12.0 g.) in small portions over 2 hours. Let stand overnight, then separate the ether layer, wash, dry and evaporate the solvent in vacuo to obtain the title product.

(b) dl-17-acetyl-13-ethyl 16 methylgona 5,16-dien- 3fi-ol, acetate.---Heat diethyleneglycol (100 ml.) to 190 C. (bath) then add dl-l7/3-acetyl-13-ethyl-l6a,l7u-methyleneazogon-5-en-3B-ol, acetate (2.5 g.) portionwise over /2 hr. Continue heating 15 minutes longer then cool and dilute with Water (200 ml.). Filter, then treat the solid in methylene chloride with anhydrous sodium sulfate and decolorizing charcoal, filter and evaporate the solvent in vacuo. Crystallize the residue from methanol to obtain the title product.

EXAMPLE 27 Pretreat a mixture of 10% palladized charcoal (1.0 g.) and absolute ethanol (100 ml.) with hydrogen at one atmosphere. Add a solution of dl-l7-acetyl-13-ethyl-l6- methylgona-S,16-dien-3fl-ol, acetate (3.00 g.) in absolute ethanol (300 ml.) and continue treating with hydrogen until one mole of the gas is absorbed. Filter and evaporate the solvent in vacuo to obtain the title product.

EXAMPLE 28 dl-l7/3-acetyl-l3-ethyl-l6a-methylgon-5-en-3B- 17a-diol and 16 8-methyl epimer thereof (a) a'l-l3-ethyl-(l-acetoxymethylidene) 16B methylgon-5-en-3fl-ol, acetate-To a solution of acetic anhydride (48 ml.) and 70% perchloric acid (0.50 ml.) in ethyl acetate (400 ml.) add dl-l7,9-acetyl-13-ethyl-16fl methylgon-5-en-3p-ol, acetate (5.00 g.), swirl the solution then let stand at about 23 C. for 5 minutes. Quench the clear reaction solution with saturated sodium bicarbonate solution, wash and dry the organic layer then evaporate the solvent in vacuo. Add methanol (300 ml.) and pyridine (1 ml.), boil for 10 minutes then cool and evaporate the solvent in vacuo. Triturate the residue with cold methanol to obtain the title product.

(b) dl13-ethyl-17-(l-acetoxyethylidene)-l6a-methylgon-5-en-3B-ol, acetate.-Dilute 3 M ethereal methyl magnesium iodide (25 ml.) with dry tetrahydrofuran (40 ml.) then under nitrogen and stirring gently reflux and remove 25 ml. of distillate. Cool, add cuprous chloride (0.40 g.), stir then add a solution of dl-17-acetyl- 13-ethylgona-5,l-6-dien-3B-ol, acetate (2.00 g.) in dry tetrahydrofuran (30 ml.) dropwise with stirring. Stir the reaction at room temperature for /2 hour then add a solution of acetyl chloride (10 ml.) in dry tetrahydrofuran (25 ml.) dropwise and with cooling. Stir the reaction a further /2 hour at room temperature then dilute with.

ether (100 ml.) and saturated ammonium chloride solution ml.). Wash and dry the ether layer and remove the solvent in vacuo. Dissolve the residue in benzene, pass the solution through a column of fiurosilicate then evaporate the benzene in vacuo. Crystallize the residue from methanol to obtain the title product.

(c) dl-17fl-acetyl-13-ethyl-16a-methylgon-5-en-3fi,17mdiol.To an ice cooled solution of dl-l3-ethyl-17-(1- acetoxy-ethylidene)-16umethylgon-5-en-3fl-ol, acetate (4.20 g.) in ether (300 ml.) add m-chloroperbenzoic acid (3.20 g.) with stirring. Stir the reaction for 4 hours, allowing it to warm to room temperature. Wash the ether layer with 5% potassium carbonate solution, water and with brine, dry and evaporate the extract in vacuo. Dissolve the residue in methanol (200 ml.) cool with an ice-bath then add a solution of potassium hydroxide (3.0 g.) in methanol (50 ml.) and stir for several minutes. Briefly warm the reaction on a steam-bath, cool and continue stirring a further /2 hour at room temperature. Add water (500 ml.) and extract the mixture with ethyl acetate. Wash, dry and evaporate the extract in vacuo to obtain the title product.

For the substrate in step (a) above substitute dl-13- ethyl 17 (l acetoxyethylidene)-16f3-methylgon-5-en- 318-01, acetate in order to obtain dl-17fl-acetyl-13-ethyl- 16 8-methylgon-5-en-3fl,17a-diol.

EXAMPLE 29 dl-17fl-acetyl-13-ethyl-17a-hydroxy-16a-methylgon- 4-en-3-one and 16/3-methyl epimer thereof Reflux a solution of dl-17fl-acetyl-13-ethyl-l6a-methylgon-5-en-3p,l7a-diol (10.0 g.) in methyl ethyl ketone (75 ml.) and benzene (500 mg.) into a water separator for 1 hour. Then add aluminum isopropoxide (8.0 g.) and continue to reflux the reaction for 3 hours. Cool, add water (500 ml.), stir /2 hour then extract the mixture with ether. Wash, dry and evaporate the extract in vacuo to get the title product. Similarly, in the above reaction substitute for the substrate dl-l7,3-acetyl-13-ethyl-16B- methylgon-5-en-3 3,17a-diol to get dl-17fi-acetyl-l3-ethyl- 17a-hydroxy-16/i-methylgon-4-en-3-one.

'EXAM PLE 3 dl-l7,8-acetyl-13-ethyl-l7u-hydroxy-16u-methy1gon- 4-en-3-one, acetate (a) a'l-17fi-acetyl-13-ethyl-16m-methylgona-3,5-diene-3, 17u-dl0l, diacetate-Prepare a fresh solution of acetic anhydride (9.6 ml.) and 70% perchloric acid (5 drops) in ethyl acetate (100 ml.) then add dl-l7fi-acetyl-13-ethyl- 17a-hydroxy-16u-methylgon-4-en-3-one (1.00 g.). Swirl the reaction for 3 minutes then quickly quench with saturated sodium bicarbonate solution. Dilute the extract with ether and wash with saturated sodium bicarbonate solution, with brine and dry. Evaporate the solvent in vacuo, dissolve the resulting oil in methanol containing a few drops of pyridine then boil gently for 5 minutes. Cool and remove the solvent in vacuo then pump the residue dry. Scratch the resulting oil with cold methanol and let stand to crystallize. Filter to obtain 0.54 g. of title product, lM.P. 131-135 C., and second crops of 0.26 g., MJP. 175-180 C. Combine the solids in methylene chloride, treat with decolorizing charcoal then filter and remove the solvent in vacuo. Crystallize the oil from methanol to get 0.66 g. of the pure title product, M.P. 193-196 C.;

Analysis.-Calcd. for C H O (percent): C, 72.86, H, 8.47. Found (percent): C, 72.91; H, 8.21.

(b) dll7B-acetyl-13-ethyl-17a-hydroxy-16a-methylgon- 4-en-3-one, acetate-"Dissolve dl-17fl-acety1-13-methyl- 16a-methylgona-3,5-diene-3,17a-diol, diacetate (1.20 g.) in tetrahydrofuran (20 ml.), dilute with methanol (20 ml.) then cool with an'ice-methanolbath. Stir and add 2% methanolic sodium hydroxide solution. Continue stirring the cool reaction for 50 minutes then add water 300 m1.) and extract the mixture with ethyl acetate-ether. Wash, dry and evaporate the extract in vacuo. Dissolve the residue in benzene and pass the solution through a short'column of neutral, anhydrous alumina. Remove the benzene in vacuo then dissolve the resulting oil inrnethylene'chloride, treat with decolorizing charcoal and filter.- 'Remove the methylene chloride in vacuo and crystallize the resulting oil with the aid of isopropanol-hexane. Filter to obtain 0.45 g. of the pure title product as colorless prisms, MP. 191-193 C.;

A511. 5.77, 5.85 and 5.97M; A539. 238 m,u (e 17,600).

Analysis.Calcd. for C H O (percent): C, 74.57; H, 8.87. Found (percent): C, 74.79; H, 8.67.

For the substrate in the above reaction, substitute dl- 17o acetyl 13 ethyl-17a-hydroxy-l6fl-methylgon-4-en- 3-one in order to obtain dl-17fi-acetyl-13-ethyl-17a-hydroxy-l6,8-methylgon-4-en-3-one, acetate.

EXAMPLE 31 al-17B-acetyl-l7a-acetoxy-13-ethyl-16a-methylgona-4, 6-dien-3-one and 16p-methyl epimer thereof To a solution of dl-17B-acetyl-13-ethyl-16a-methylgona- 3,5-diCI16-3,l7a-di0l, diacetate (1.0 g.) in acetone (20 ml.) add a solution of sodium acetate (05 g.) and glacial acetic acid (0.5 g.) in water (5 ml.) and acetone (25 ml.). Cool the reaction to 0 C. then add N-bromoacetamide (1.5 g.) and continue stirring at 0 C. for 3 hours. Pour the reaction into brine, extract with ether then wash, dry and evaporate the solvent below room temperature in vacuo to about 10 ml. Add dimethylformamide (30 ml.) and calcium carbonate (1.0 g.) and heat the reaction to reflux allowing the ether to evaporate. Reflux the mixture for 1 hour, cool and filter. Dilute the filtrate with water then extract with ether and wash, dry and evaporate the solvent in vacuo to obtain the title product.

In the above reaction substitute for the substrate, dll7 8-acetyl-13-ethyl-16fl-methylgona-3,5-dien 3,17oc-dl0l, diacetate to obtain dI-IZB-acetyl-17a-acetoxy-13-ethyl- 16,B-methylgona-4,6-dien-3-one.

EXAMPLE 32 dl-17,3-acetyl-17a-acetoxy 6 chloro-13-ethyl-l6a-methylgona-4,6-dien-3-one, the 6-bromo and 6-fluoro analogs, and the 16fi-methyl epimer thereof Dissolve dl-17p-acetyl-17m-acetoxy-13-ethyl-1'6a-methylgona-4,6-dien-3-one (3.0 g.) in ether (300 ml.) then add m-chloroperbenzoic acid (4.0 g.) and stir the reaction at about 23 C. for 20 hours. Wash the ether extract with 5% potassium carbonate solution, water and brine, then dry and evaporate the solvent in vacuo. Dissolve the residue in glacial acetic acid ml.) then bubble in hydrogen chloride gas until the solution is saturated with the gas. Stir the reaction for 16 hours at about 23 C. then add water (50 ml.) and continue stirring for 1 hr. Extract the mixture with ether then wash the extract well with water then with-5% sodium carbonate solution. Dry the extract then evaporate the solvent in vacuo. Dissolve the residue in benzene and pass the solution through a short column of anhydrous, neutral alumina. Evaporate the benzene in vacuo to obtain the title product.

For the substrate in the above reaction substitute dll7fi-acetyl-l7a-acetoxy 13 ethyl-16B-methylgona-4,6- dien-3-one to obtain dl-17/3-acetyl-l7a-acetoxy-6-chloro- 13-ethyl-l6,8-methylgona-4,6-dien-3-one.

For hydrogen chloride in the above reaction substitute hydrogen bromide and hydrogen fluoride. There are obtained.

dl-17 3-acetyl-17a-acetoxy-6-bromo-13-ethyl-16a-methylgona-4,6-dien-3-one;

dl-17fl-acetyl-17u-acetoxy-13-ethyl-6-fluoro-1Got-methylgona-4,6-dien-3-one;

dl-17 8-acetyl-17u-acetoxy-6-bromo-13-ethyl-16fi-methylgona-4,6-dien-3-one; and I 

